7alpha, 17, 17-trimethyl-18-nor-delta13(14)-steroids of the androstane series



3,341,411 7a,17,17-TRlMETHYL-l8-N0R-A -STEROIDS OF THE ANDROSTANE SERIES J. Allan Campbell and John C. Babcock, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo,

Mich., a corporation of Delaware No Drawing. Filed Apr. 7, 1965, Ser. No. 446,384 14 Claims. (Cl. 167-65) This invention relates to novel steroid compounds, especially to 7a,17,17-trimethyl-18-nor-4,13(14)-androstadiene, its corresponding 4-saturated, Zea-methyl, 4(a and ,8)-methyl, 211,4(oc and 3)-dimethyl derivatives and the 19-nor counterparts of the foregoing compounds having the formula CH3 CH3 VI CH3 radical C=O),

OZ and Q Z being selected from the group consisting of hydrogen, acyl and tetrahydropyranyl.

The compounds of the present invention and the processes for their production are illustratively represented by the following sequence of formulae:

OH "CHt 1 3 Rr-p Y United States Patent Ofiice 3,341,411 Patented Sept. 12, 1967 wherein f, 4(5), R, R R and Y have the same meaning as above.

The compounds of Formula III of the present invention have anabolic activity of improved therapeutic ratio of the former versus the latter. They also possess antifertility, anti-androgenic and anti-estrogenic activities. They exhibit CNS-regulating activity and antimicrobial properties. They also have the ability to reduce the level of cholesterol, decrease platelet adhesiveness, and decrease clot lysis time in the blood and consequently are of therapeutic value in the treatment or prevention of atherosclerosis and thromboembolic disease. The foregoing properties make the new compounds useful in medical and veterinary practice.

The compounds of Formula III of the invention can be prepared and administered to mammal, birds, humans, and animals, in a wide variety of oral or parenteral dosage forms, singly or in admixture with other coacting compounds. They can also be administered with a pharmaceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills, or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups, or elixirs.

The novel compounds of this invention, embraced by Formula III of the above flow-sheet, are prepared by subjecting the steroids of Formula II to acid catalyzed (Wagner-Meerwein) rearrangement.

The A -17,17-dimethyl compounds (III) are prepared from the corresponding 13-saturated --17a-methyl-17,B- hydroxy compounds (II) by the heating of the latter (e.g., at refluxing temperatures) in an inert organic solvent such as methanol, ethanol, dioxane or other water miscible solvent, in the presence of an acid (e.g., hydrochloric, sulfuric or hydrobromic) for a prolonged period (e.g., from about 3 to about 6 hours), preferably in an inert atmosphere such as nitrogen. The products (III) are recovered by conventional procedures such as crystallization or chromatography, or a combination of these.

The 7a,17,17-trimethyl compounds of Formula III of the invention are prepared from the known 7a-methyl-4- androstene starting materials of Formula I, which are synthesized in the manner described in I. Amer. Chem. Soc. 81, 4069. The corresponding ZaJu-dimethyl compounds (I) are produced in accordance with the procedures of US. Patent 2,923,720.

The methods for obtaining the compounds of Formula II from those of Formula I are set forth below.

The starting materials of Formula I are readily reduced by known methods to the corresponding 7u,17a-dimethyl (and 2a,70t,170t-trlnl6Ihy1)-3(0t and fl,)-hydroxy-5(a and B)-androstanes (II). These methods can be employed to produce the 3a-hydrOXy-SB-andmstanes, 3,5-hydroxy-5aandrostanes, 3a-hydroxyJfi-andrustams and 3,B-hydroxy- 5fl-androstanes embraced by Formula I.

The a d-unsaturated ketones (I) can be reduced with metal (preferably lithium) in ammonia to yield the corresponding 3-keto-5a-androstanes (II) and the reduction stopped at this stage if reagents such as t-butyl alcohol or ammonium chloride are employed at the end of the reaction (in the manner described in J. Amer. Chem. Soc., 81, 2386 for the conversion XX- XXV). The same publication shows that continued treatment following the addition of methanol instead of t-butyl alcohol or ammonium chloride, leads directly to the saturated 313- hydroxy-wandr-ostanes (II). For example, when the reduction of a compound such as 7amethyl l7fi-hydroxy- 4-androsten-3-one (I), e.g., with lithium in ammonia, i discontinued at the point where 7u-methyl-l7B-hydroxy- 5a-androstan-3-one (II) is formed, it can be further reduced (e.g., with sodium borohydride) to yield 7a-methyl- 3,8,l7fi-dihydroxy-5rat-androstane (II). On the other hand, the reduction of a 3-lceto-4-androstene (I) directly to the corresponding 3fl-hydroxy-5a-androstane (II), without isolation of the 3-keto-5u-androstan-3-one (II), can be carried out in accordance with the above-noted publication.

The 3-keto-7a-methyl (and 206,70t-dl11'16th3/1)-50t-2ll'ldf0- stanes (III) can be reduced to yield a mixture of 3-(0t and [3)-hydroxy-5a-androstanes (II). For example, treating a 7a,17u-dimethyl-17fi-hydroxy-Swandrostan-3-one l7-acylate (II) with lithium aluminum tri-t-butyoxyhydride in a solvent (e.g., tetrahydro-furan) yields a corresponding 7u,17a dimethyl 3a,17a-dihydroxy-5a-androstan 17- acylate (II) and a corresponding 7 a,17ot-dimethyl-3,8,17 DC- dihydroxy-5u-androstane 17-acylate II).

Most of the metal (lithium)-ammonia reductions of the 3-keto-4-androstenes (I) are conducted in the presence of co-solvents such as ether, dioxane or tetrahydrofuran.

Conversion of the compounds of Formula I to a variety of 3(a and 5)-hy-droxy-5a-androstanes can be carried out by procedures known in the steroid art. For example, after reduction of a compound of Formula I, such as a 70,17a-dimethyl-17fi-hydroxy-4-an-drosten-3-one 17-acylate (I), e.g., with lithium in ammonia in a solvent such as tetrahydrofuran, to yield a compound of Formula II, such as a corresponding 7a,Wot-dimethyl-17fi-hydroxy- 5ix-androstan-3-one 17-acylate (ill), the thus produced compound -(II) is treated with a reducing agent to obtain compounds such as a corresponding 7a,l7a-dimethyl- 3a,17B-dihydroxy-5oc-androstane 17-acylate (II) and acorresponding 70:,17oc dimethyl-3,8,l75-dihydroxy-5a-androstane l7-acylate II).

The conversion of the 3-ketone of Formula II to the corresponding 3(a. and fi)'hydroxy compounds is carried out using a reducing agent, for example, lithium tri-tbutoxyhydride, lithium aluminum triethoxyhydride, sodium borohydride, potassium borohydride, diborane, and the like, in an inert organic solvent, for example, tetrahydrofuran, ether, diethyleneglycol dimethyl ether, and the like. Advantageously, the reaction is carried out at temperatures of from 0 to 100 C. for from about A to about 2 hours, with a temperature of 25 C. for about /2 hour being preferred. The 3(OL and B)hydroxy compounds of Formula II are recovered following their formation by fractional crystallization, chromatography of the total crude reaction product on acid washed alumina, Florisil (synthetic aluminum silicate), silica gel (precipitated silicic acid granules), or silicic acid, with elution by commercial hexanes containing increasng amounts of acetone or benzene containing increasing amounts of methanol, Craig countercurrent partition separation, column partition chromatography, preparative paper chromatography, thin-layer chromatography, or a combination of these methods.

The conversion of the compounds of Formula II, such as a 7a,l7a-dimethyl-3u,l7B-dihy-droxy-5zit-androstane l7- acylate, and a 7a,l7oi-dimethyl-3fi,l7fi-dihydroxy-5ot-androst-ane l7-acylate, to the corresponding l7f3-ihydroxy compounds such as. 7a,17ocdlmefhyl3a,17fl-dlhyd10Xy-50candrostane and 7u,l7a-dimethyl-3,8,l7fi-dihy-droxy-5a-androstane, is carried out according to procedures well known in the art for the conversion of androstane l7-acylates to androstane 17-alcohols as shown in U.S. Patent 2,849,464.

The 7a,l7a-dimethyl (and 2a,7a,l7ot-trimethyl)-3-keto- 4-androstene compounds of Formula I, can be converted to the corresponding SB-androstanes (II) by hydrogenation of the A -bond. For example, treating a compound such as 2a,7ot,17u-trimethyl-17B-hydroxy-4-androsten-3- one (I) in a solvent (e.g., 95% ethyl alcohol) in the presence of a catalyst (e.g., 5% palladium on charcoal) with hydrogen until one mole equivalent is consumed, yields a compound such as 20,7rx,17a-trimethyl-17fi-hydroxy-5fi-androstan-3-one (II). Isolation of the desired compound from the reaction mixture and its subsequent purification is accomplished by methods well known in the art. For example, the catalyst is removed from the reaction mixture by filtration through a bed of Celite (diatomaceous earth), the filtrate concentrated to dryness, chromatographed on an adsorbent column (e.g., Florisil), eluted with solvents such as acetone-Skellysolve B (hexanes) and recrystallized from solvents such as the aforesaid pair of eluants.

The :,17ot-dlIIl6ihYl (and 2a,7ot,l7u-trimethyl)-3-keto- Sit-androstanes of Formula II can be converted to the corresponding 3ot-hydroxy-5/3-androstanes (II) by hydrogenation of the 3-keto group. For example, treating a compound such as 2a,7a,l7a-trimethyl-17fl-1hydroxy-55- androstan-3-one (=11) in a solvent (e.g., tetrahydrofuran) with a reducing agent (e.g., lithium aluminum tri-t-butoxyhydride) or sodium borohydride at low temperature (e.g., 0 C.), with agitation (e.g., stirring), yields a compound such as 2ot,7a,l7ot-trimethyl-3a,l7B-dihydroxy-5B-androstane (II). The reaction mixture containing the desired compounds of Formula II is stored at low temperature (e.g., --15 C.) for about 18 hours. Dilute acetic acid is added until the inorganic materials are coagulated. The organic phase is decanted, dried over a dehydrating agent such as magnesium sulfate, filtered, concentrated to dryness and recrystallized from solvent to yield the 3a-hydroxy-5a-androstane (II), or alternatively, purified by chromatography with a Florisil column.

In order to produce the 3-desoxy compounds of Formula II, wherein the 5-hydrogen atom is m-oriented, the 3-oxygenated compounds are first converted to their corresponding 3-thioketal derivatives in the manner of J. Amer. Chem. Soc. 76, 1945, namely, by reaction with an alkanedithiol (such as ethanedithiol) in the presence of an organic acid and a strong Lewis acid catalyst (e.g., boron trifluoride etherate); desulfurization is accomplished by hydrogenation of the 3-thioketal group (e.g., with sodium metal in liquid ammonia or with hydrogen in the presence of a catalyst such as Raney nickel) to yield a corresponding 3-desoxy compound (II), such as 7a,17a-dimethyl-19-nor-17fi-hydroxy-5a-androstane (II).

Toproduce the 3-desoXy-5/3-androstanes of Formula II, the 4-androstene-s of Formula I are first converted to their corresponding 3-thioketal derivatives followed by desulfurization (in the same manner as in the immediately preceding paragraph) to yield a compound such as 70L,17OL dimethyl l9-nor-l7fi-hydroxy 4-androstene. A thus produced 3-desoxy-A -steroid can be dissolved in a solvent (e.g., alcohol) with a catalyst such as 5% palladium on charcoal or Adams (platinum dioxide) catalyst, and hydrogenated until one mole equivalent of hydrogen is consumed to yield a compound such as 70,17ocdimethyl-19-nor-l7 B=hydroxy-5/3-androstane ("II) The catalyst is filtered off and the filtrate concentrated to dryness. The residue of the SB-hy-drogen compound (II) is puritfied by recrystallization or chromatography with a column of Florisil.

A compound of Formula II, such as 7a,l7a-dimethyl- 3a,17,8-dihydroxy-5rat-androstane 17-acylate (II) can be 5 transformed to a corresponding 3-dihydropyranyl ether (II) by the two following reactions.

(1) The conversion of a compound of Forumla II, such as 7oz,l7a-dimethyl-3a,17fi-dihydroxy-5a-androstane 17- acylate, to compounds such as 7a,17u-dimethyl-3a,17fi-dihydroxy-5a-androstane 3-dihydropyranyl ether 17-acylate (II) is carried out by reacting a corresponding compound of Formula II with dihydropyran in the presence of a Lewis acid, such as boron trifluoride etherate, p-toluenesulfonic acid, sulfuric acid, zinc chloride, phosphorous oxychloride, and the like. Advantageously, the reaction can be carried out in an organic solvent, such as ether, benzene, and the like. The reaction is carried out at temperatures of from about C. to about 80 C., with a temperature of 25 C. being preferred. The thus obtained 3-dihydropyranyl ether 17-acylate compounds of Formula II are recovered from the reaction mixture by conventional methods such as, for example, dilution of the reaction mixture with water, extraction with a water irnmiscible solvent, such as methylene chloride, ethyl acetate, benzene, toluene and the like, or any of the methods described above for the recovery of the 3 (a and fi)-hydroxy compounds of Formula II. Alternatively, the entire crude product obtained in this reaction 1) can be used in the subsequent hydrolysis of step (2).

(2) The hydrolysis of the compounds of Formula II, such as 7a,l7u-dimethyl-3a,17,8-dihydroxy-5a-androstane S-dihydropyranyl ether 17-acylate, to compounds such as 711,170t-dlmelIllyl-30t,17,3-(11hydI'OXY-SOL-aIIdIOSIZIHe 3-dihydropyranyl ether, is carried out in an alkaline aqueous medium using relatively water soluble alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth hydroxides, e.g., sodium or potassium carbonate, sodium or potassium hydroxide, calcium hydroxide, and the like, preferably potassium hydroxide. Advantageously, there is added to the alkaline aqueous medium an inert water-miscible organic solvent, such as methanol, ethanol, isopropyl alcohol and the like, with methanol being preferred. The reaction is carried out at temperatures of about 10 C. to about 100 C. for from about 1 to about 20 hours. The 3-dihydropyranyl ether-17B-hydroxy compounds of Formula II are recovered from the reaction mixture by the methods described above for the recovery of the corresponding 17-acylate compounds of Formula II.

The 4,7a,l7,l7-tetramethyl compounds of Formula III of the invention are prepared from the known 7a-methyl- 4-androstene starting materials of Formula I, which are synthesized in the manner described in J. Amer. Chem.- Soc. 81, 4069. The corresponding 2u,7ot-dimethyl starting compounds (I) are produced in accordance with the procedures of U8. Patent 2,923,720.

The 4,7a,l7u-trimethyl and 2a,4,7a,17a-tetramethyl compounds of Formula II, wherein the 4(5)-carbon atom linkage is a double bond, are prepared in accordance with Canadian Patent No. 676,599 and Australian Patent No. 244,970. A 3-oXo-A -starting steroid of Formula I is condensed with formaldehyde or paraformaldehyde and a thiol in the presence of a basic catalyst to yield a corresponding 4-organothiomethyl-3-oxo-A -steroid (I'). It is not necessary to isolate the 4-organothiomethyl compounds (I') in crystalline form, as they are generally formed in high yield, so that the total product can be employed in a desulfurizationstep resulting in the production of the various 4'methylated compounds embraced by Formula II.

Desulfurization of the 4-organothiomethyl intermediates (I') can be carried out by treating a solution of the organothiomethyl compound with Raney nickel of a suitable reactivity. The preferred solvent is acetone, but other ketonic solvents such as butan-Z-one or cyclohexanone can be employed, either alone or diluted with an inert solvent such as a lower alkanol containing up to carbon atoms. The reactivity of the Raney nickel must first be adjusted so as to prevent saturation of the 4:5-ethylenic linkage, which may occur if a highly active Raney nickel is used. Raney nickel, as ordinarily prepared, may be suitably deactivated by preliminary heating in the ketonic solvent, preferably acetone, in which the desulfurization is to be effected, preferably in a slow stream of nitrogen to facilitate removal of the hydrogen gas which is evolved from the nickel. The thiomethyl compound (I') is then added to the suspension of the deactivated Raney nickel, and heating is continued until desulfurization is completed, when the corresponding 4,7ot,l7a-trimethyl or 2a,4,7cc,17atetramethyl-l7,8-hydroXy-3-oXo-A -steroid (II) can be isolated, for example, by filtration to remove the nickel and evaporation of the filtrate.

When the thiomethyl compound (1') contains a readily oxidizable hydroxyl group, such as a 17,8-hydroxyl group, it is advisable to protect this group by formation of a derivative such as the acetate or propionate prior to the desulfurization reaction, in order to avoid partial oxidation of the hydroxyl group to an OX0 group, which may occur, with concomitant reduction of a part of the ketonic solvent to the corresponding alcohol, under the catalytic influence of Raney nickel. The hydroxyl group can be regenerated after desulfurization, if desired, by hydrolysis of the ester, for example, with alcoholic: alkali.

An alternative method for converting the compounds of Formula I to the corresponding 4-alkyl derivatives (II) is described in US. Patent 3,070,612. In accordance with the process disclosed therein, the starting materials of this application, such as 7a,17a-dimethy1-17fl-hydroxy- 4-androsten-3-one (I), or the Zoe-methyl counterpart (I) thereof, can be treated with a secondary cyclic amine to produce the S-enamine of the corresponding starting material. The 3-enamine thus produced can then be reacted with an alkylating agent to produce the 4-alkyl-3-enamine of the corresponding starting material; these compounds on hydrolytic removal of the enamine group yield the corresponding 4-alkyl-3-keto compounds, i.e., the 4-alkyl- 7a,17a-dimethyl-17fi-hydroxy-4-androsten-3-ones (II) or the Zea-methyl counterpart thereof (II).

In order to produce the A -3-desoxy compounds of Formula II, the A -3-keto compounds of Formula II are first converted to their corresponding 3--thioketal derivatives in the manner of J. Amer. Chem. Soc. 76, 1945, namely, by reaction with an alkanedithiol (such as ethanedithiol) in the presence of an organic acid and a strong Lewis acid catalyst (e.g., boron trifluoride etherate); desulfurization is accomplished by hydrogenation of the 3- thioketal group (e.g., with sodium metal in liquid ammonia or with hydrogen in the presence of a catalyst such as Raney nickel) to yield a corresponding 3-desoxy compound (II), such as 4,7a,17a-trimethyl-19-nor-17,B-hydroXy-4-androstene (II).

The 4,70,17u-trimethyl-17,6-hydroxy-4-androsten-3-ones (II) and 2a,4,7u,17a-tetrarnethyl-l7fl-hydroxy-4-androsten-3-ones (II), produced as above, are readily reduced by known methods to the corresponding 4(a and fi),7a, 17a-trimethyl-17B-hydroxy-5(a and /i)-androstan-3-ones (II) and 2a,4( x and B),7a,l7a-tetramethyl-l7B-hydroxy- 5 (a and B)-androstan-3-ones (II); further reduction yields the corresponding 3(a and B)-hydroxides (II). The foregoing 4(a and ,8),7a,l7a-trimethyl and 2cc,4(oc and B),7oc, 17a-tetrarnethyl-5(rx and B)-androstanes embraced Within Formula II of the flow-sheet, above, can be converted to the steroids included within Formula HI therein, in the manner described above.

The c p-unsaturated ketones (II) can be reduced with metal (preferably lithium) in ammonia to yield the corresponding S-keto-Sa-androstanes (II) and the reduction stopped at this stage if reagents such as t-butyl alcohol or ammonium chloride are employed at the end of the reaction (in the manner described in J. Amer. Chem. Soc. 81, 2386 for the conversion XX- XXV). The same pub lication shows that continued treatment following the addition of methanol instead of t-butyl alcohol or ammonium chloride, leads directly to the saturated 3,6-hydroxy-5uandrostanes (II). For example, when the reduction of a compound such as a 4(a and p),7a,17a-trimethyl-17flhydroxy-4-androstene-3-one (II), e.g., with lithium in ammonia, is discontinued at the point where a 4(a and ,B), 7a,17u-trimethyl-17fl-hydroxy-5u-and-rostan-3-one (II) is formed, it can be further reduced (e.g., with sodium borohydride), to yield a 4(oc and [3), 7a,l7a-trimethyl- 3B,l7fl-dihydroxy-5(rt-androstane (II). On the other hand, the reduction of a 3-keto-4-androstene (II) directly to the corresponding BB-hydroxy-Su-androstane (II), without isolation of the 3-keto-5a-androstan-Zi-one (II), can be carried out in accordance with the above-noted publication.

The 3-keto-4 (a or f3,)7a,17a-trirnethyl(and 204,4[04 or p8],7a,17a-tetramethyl)Jar-androstanes (II) can be reduced to yield a mixture of 3(a and fl)-hydroxy-5a-androstanes (II). For example, treating a 4(oc or [3), 7a,l7ottrimethyl-175-hydroxy-5wandrostan-3-one 17-acylate (II) with lithium aluminum tri-t-butoxyhyd-ride in a solvent (e.'g., tetrahydrofuran) yields a corresponding 4(a or 18),7a,l7a-trimethyl-3a,l7a dihydrOXy-Sa-androstane 17- acylate (II) and a corresponding 4(0L or ,B),70t,170L-III- methyl-36,l7u-dihydroxy-Six-androstane l7-acylate (II).

Most of the metal (lithium)-ammonia reductions of the 3-keto-4-androstenes (II) are conducted in the presence of co-solvents such as ether, dioxane or tetrahydrofuran.

Conversion of the A -compounds of Formula II to a variety of 3(oc and 8)-hydroxy-5a-androstanes can be carried out by procedures known in the steroid art. For example, after reduction of a A -cmpound of Formula II, such as a 4(oc or )8), 7a,17ot-trimethyl-17fl-hydroxy-4- androsten-3-one l7-acylate (II), e.g., with lithium in ammonia in a solvent such as tetrahydrofuran, to yield a compound of Formula II, such as a corresponding 4(oc or ,8),7oc,17oc-trimethyl-17,8 hydroxy-u-androstan-3-one 17- acylate (II), the thus produced compound is treated with a reducing agent to obtain compounds such as a corresponding 4(oc or 18) ,7'oc,l7ot-trimethyl-3a,17fi-dihydroxy-5 aandrostane 17-acylate (II) and a corresponding 4(a or 5),7a,l7a-trimethyl-3fl,l7fi dihydroxy-5a-androstane 17- acylate (II).

The conversion of the 3-ketones of Formula II to the corresponding 3(oc and ;8)-hydroxy compounds (II) is carried out using a reducing agent, for example, lithium tri-t-butoxyhydride, lithium aluminum triethoxyhydride, sodium borohydride, potassium borohydride, diborane, and the like, in an inert organic solvent, for example, tetrahydrofuran, ether, diethyleneglycol dimethyl ether, and the like. Advantagcously, the reaction is carried out at temperatures of from 0 to 100 C. for from about A to about 20 hours, with a temperature of 25 C. for about /2 hour being preferred. The 3(oc and ,8)-hydroxy compounds of Formula II are recovered following their formation by fractional crystallization, chromatography of the total crude reaction product on acid washed alumina, Florisi-l (synthetic aluminum silicate), silica gel (precipitated silicic acid granules), or silicic acid, with elution by commercial hexanes containing increasing amounts of acetone or benzene containing increasing amounts of methanol, Craig countercurrent partition separation, column partition chromatography, preparative paper chromatography, thin-layer chromatography, or a combination of these methods.

The conversion of the compounds of Formula II, such as a 4(a or B),7ot,17a-trimethyl-3a,17;3-dihydroxy-5a-androstane l7-acylate and a 4(u or B),7a,17u-trimethyl-3{3, 17,6-dihydroxy-5ot-androstane 17-acylate to the corresponding 17/3-hydroxy compounds such as 4(a or B),7a,17utrimethyl-3ot,l7B-dihydroxy-5a-androstane and "4(oc or [3), 7a,17a-trimethyl-3B,17fi-dihydroxy-5tat-androstane, is carried out according to procedures well known in the art for the conversion of androstane 17-acylates to androstane l7-alcohols as shown in U .8. Patent 2,849,464.

A compound such as 4(a or [3),7a,17a-trimethyl-3a,17fldihydroxy-5a-androstane 17-acylate (II) can be transformed to a corresponding 3-dihydropyranyl ether (II) by the two following reactions.

(1) The conversion of a compound of Formula II, such as 4(a or ,8),7u,l7a-trimethyl-3a,17B-dihydroxy-5aandrostane 17-acylate, to compounds such as 4(oc or 8), 7a,l7ot-trimethyl-3a,17/3-dihydroxy-5wandrostane S-dihydropyranyl ether l7-acylate (II) is carried out by reacting a corresponding 3(a or fl)-hydroxy compound with dihydropyran in the presence of a Lewis acid, such as boron trifluoride etherate, p-toluenesulfanic acid, sulfuric acid, zinc chloride, phosphorous oxychloride, and the like. Advantageously, the reaction can be carried out in an organic solvent, such as ether, benzene, and the like. The reaction is carried out at temperatures of from about 0 C. to about C., with a temperature of 25 C. being preferred. The thus obtained 3-dihydropyranyl ether l7-acylate compounds of Formula II are recovered from the reaction mixture by conventional methods such as, for example, dilution of the reaction mixture with water, extraction with a water immiscible solvent, such as methylene chloride, ethyl acetate, benzene, toluene and the like, or any of the methods described above for the recovery of the 3(0: and B)-hydroxycompounds of Formula 11. Alternatively, the entire crude product obtained in this reaction (1) can be used in the subsequent hydrolysis of step (2).

(2) The hydrolysis of the compounds of Formula II, such as 4(oc or [3),7,l7a-trimethyl-3u,17/3-dihydroxy-5uandrostane B-dihydropyranyl ether l7-acylate, to compounds such as 4(oc or 8),704,17a-trimethyl-3u,17,3-dihydroxy-Su-androstane 3-dihydropyranyl ether, is carried out in an alkaline aqueous medium using relatively water soluble alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth hydroxides, e.g., sodium or potassium carbonate, sodium or potassium hydroxide, calcium hydroxide, and the like, preferably potassium carbonate. Advantageously, there is added to the alkaline aqueous medium an inert watermiscible organic solvent, such as methanol, ethanol, isopropyl alcohol and the like, with methanol being preferred. The reaction is carried out at temperatures of about 10 C. to about 100 C. for from about 1 to about 20 hours. The 3-dihydropyranyl ether-17,6-hydrox-y compounds of Formula II are recovered from the reaction mixture by the methods described above for the recovery of the corresponding 17-acylates of Formula II.

The 4(a or /8),7a,17a-trimethyl(and 2a,4[a or 51,70, l7oc-tetramethyl)-3-keto-4-androstene compounds of Formula II can be converted to the corresponding 55- androstanes (II) by hydrogenation of the A -bond. For example, treating a compound such as 20c,4(a or fi),7oc, 17oc-tetramethyl-l7B-hydroxy-4-androstene-3-One (II) in a solvent (e.g., ethyl alcohol) in the presence of a catalyst (e.g., 5% palladium on charcoal) with hydrogen until one mole equivalent is consumed, yields a compound such as 200,4(0: or ,8),7a,l7a-tetramethyl-17,6-hydroxy-5fiandrostan-3-one (II). Isolation of the desired compound from the reaction mixture and its subsequent purification is accomplished by methods well known in the art. For example, the catalyst is removed from the reaction mixture by filtration through a bed of Celite (diatomaceous earth), the filtrate concentrated to dryness, chromatographed on an adsorbent column (e.g., Florisil), eluated with solvents such as acetone-Skellysolve B (hexanes) and recrystallized from solvents such as the aforesaid pair of eluants.

The 4(0c or B),7a,17a-trimethyl (and 204,4[a or {3],7a, l7a-tetramethyl) -3-keto-5B-androstanes of Formula II can be converted to the corresponding '3a-hydroxy-5/3- androstanes (II) by hydrogenation of the 3-keto group. For example, treating a compound such as 2oc,4(a or ,8), 7a,17oc-tetramethyl-l7B-hydroxy-5 e-androstan-ia-one (II) in a solvent (e.g., tetrahydrofuran) with a reducing agent (e.g., lithium aluminum tri-t-butoxyhydride) at low temperature (e.g., 0 C.), with agitation (e.g., stirring),

9 yields a compound such as 2a,4(ot or l3),7a,17atetramethyl-3a,17 8-dihydroxy-5fi-androstane (H). The reaction mixture containing the desired fla-hydroxy compounds for Formula II is stored at low temperature (e.g., 15 C.) for about 18 hours. Dilute acetic acid is added until the inorganic materials are coagulated. The organic phase is decanted, dried over a dehydrating agent such as magnesium sulfate, filtered, concentrated to dryness and recrystallized from solvent to yield the 3Bt-hydIOXy-50tandrostane (II), or alternatively, purified by chromatography with a Florisil column.

In order to produce the 3-desoxy-5u-androstane compounds of Formula II, the Soeandrostane compounds of Formula II are first converted to their corresponding '3- thioketal derivatives in the manner of J. Amer. Chem. Soc. 76, 1945, namely, by reaction with an alkanedithiol (such as ethanedithiol) in the presence of an organic acid and a strong Lewis acid catalyst (e.g., boron trifluoride etherate); desulfurization is accomplished by hydrogenation of the 3-thioketal group (e.g., with sodium metal in liquid ammonia or with hydrogen in the presence of a catalyst such as Raney nickel) to yield a corresponding S-desoxy compound (II), such as 4(oc or B),7u,17cttrimethyl-19-nor-17fl-hydroxy-5o-androstane (II).

To produce the 3-desoxy-5fl-androstanes of Formula II, the 4-androstenes of Formula II are first converted to their corresponding 3-thioketal derivatives followed by desulfurization (in the same manner as in the immediately preceding paragraph) to yield a compound such as 4(1): or 8) ,7a,17a-trimethyl-19-nor-17/3-hydroxy-4-androstene. A thus produced 3-desoxy-A -steroid can be suspended in a solvent (e.g., 95% alcohol) with a catalyst such as palladium on charcoal, or Adams (platinum dioxide) catalyst, and hydrogenated until one mole equivalent of hydrogen is consumed to yield a compound such as 4(a or 13),7a,17a-trimethyl-19-nor-17fi-hydroxy-5B-androstane (II). The catalyst is filtered off and the filtrate concentrated to dryness. The residue of the Sfi-hydrogen compound (II) is purified by recrystallization or chromatography with a column of Florisil.

A solution of 1 g. of 7a,17a-dimethyl-17/3-hydroxy-4- androstan-3-one (7a,17a-dimethyltestosterone) (I) (prepared as in J. Amer. Chem. Soc. 81, 4069) in 250 ml. of 95 ethyl alcohol is reacted with hydrogen using 5% palladium on charcoal catalyst until 1 mole equivalent of hydrogen is absorbed. The catalyst is removed by filtration through a bed of Celite (diatoma-ceous earth). The filtrate is concentrated to dryness, chromatographed through a Florisil column and recrystallized from a mixture of acetone and Skellysolve B to give 7a,l7a-dimethyl-17,B- hydroxy-Sfi-androstan-S-one (1).

Following the procedure of Example 1, but substituting for 7a,l7udimethyl-17fi-hydroxy-4-androsten-3-one (I), the following representative starting materials:

( 1) 7a,17x-dimethyl-19-nor-17B-hydroxy-4-androsten- 3-one (I) and (2) 7a,17a-dimethyl-19-nor-17 3-hydroxy-4-androsten- 3-one-17-acetate (I),

yields respectively, 1 7a, 17 a-dimethyl-19-nor-17,8-hydroxy-5 3-androstan- 3-one (II) and (2) 7a,17a-dimethyl-19-nor-l7fl-hydroxy-5fl-androstan- 3-one-17-acetate (II).

EXAMPLE 2 2a,7a,1 7a-trimethyl-1 7,6-hydr0xy-4-androsten-3-0ne (I) (a) To a solution of 50 g. of 7a,l7u-dimethyl-17B- hydroxy-4-androsten-3-one (70c,17u-dimethyltest0ster0ne) (I) (prepared as in J. Amer. Chem. Soc. 81, 4069) in 750 ml. of t-butyl alcohol, warmed to 55 C. in a nitrogen atmosphere, 50 ml. of ethyl oxalate and 65 ml. of 25% sodium methoxide solution was added with stirring. Stirring was continued for about 20 minutes after which 750 ml. of ether was added. The mixture was filtered and the solid off-yellow glyoxalate dried in a vacuum oven to give 46 g. of crude material. A mixture of the crude glyoxalate, g. of potassium carbonate, 150 ml. of methyl iodide and 1250 ml. of acetone was stirred and heated under reflux for about 24 hours. Approximately 500 ml. of liquid was distilled oft and the remaining mixture filtered. The filter cake was washed. with acetone and the combined mixture filtered. The cake was washed with additional acetone and the combined filtrate evaporated at reduced pressure to an amber gum which was dissolved in 625 ml. of methanol purged with nitrogen and treated with 50 ml. of 25% sodium methoxide solution. After about 2 hours, 1400 ml. of saturated sodium chloride solution was added, and the mixture extracted with methylene chloride. The extract was dried and the solvent evaporated. The crude gummy product was purified via chromatography on a 2.5 kg. column of Florisil. A mixture composed of 6% of acetone and the remainder Skellysolve B eluted 13.34 g. of crystals, which on recrystallization from acetone-Skellysolve B yield 11.53 g. of the desired product melting at 158 to 159 C. A portion of this material was recrystallized from the same solvent pair to provide an analytical sample of pure 2a,7ac,17ot trimethyl-17;8-hydroxy-4-androsten-3-one (I) melting at 158 to 159 C.:

Rig; 242 Ill/.4

e=15,500; 'y 3435, 1665, 1622, 12 00, 1166, 1075 cm." (index I-l0,881). Depression of the melting point of the product (I) occurred on mixture with the starting material (I).

Analysis.Calcd. for C H O Found: C, 79.60; H, 10.48.

Following the procedure of (a) of Example 2, but substituting for the starting steriod 7a,l7a-dimethyl-17flhydroxy-4-androsten-3-0ne (I), the following representa tive starting materials:

(2) 7a,l7rx-dimethyl-19-nor-17,8-hydroxy-4-androsten- 3-one 17-acetate (I) yields, respectively,

- andro- EXAMPLE 3 7a,] 7a-dim'ethyl-17p-hydroxy-5a-androstan-3-one (II To about 1.21. of liquid ammonia, 0.8 g. of lithium wire cut in small pieces was added. After the lithium had dis solved, 10 g. of 7a,17a,-dimethyl-17,8-hydroxy-4-androsten-3-one (I) in 200 ml. of tetrahydrofuran (purified by passage through an aluminum oxide column) was added in a slow stream at reflux. The solution was refluxed for about 15 minutes, then 15 g. of olid ammonium chloride was added in small portions. The ammonia was rapidly evaporated on a steam bath. Water was added and the product extracted with ether. The ether extract was washed successively with water, dilute hydrochloric acid, water and brine, then dried over magnesium sulfate, filtered and concentrated to dryness. The amorphous solid was dissolved in methylene chloride and the solution poured onto a 250 g. Florisil column packed wet with Skellysolve B and eluted (employing 400 ml. fractions) by gradient elution between l. of a mixture comprising 2% acetone and 98% Skellysolve B and 5 l. of a mixture of 12% acetone and 88% Skellysolve B to give 5.25 g. of material melting at 155 to 158 C. A second crop weighing 1.3 g. melting 150 to 153 C. was obtained from aqueous methanol. Recrystallization of 200 mg. of the first crop material from acetone-Skellysolve B provided material for analysis of the desired product, 7a,17a-dimethyl-17B-hydroxy-5m-androstan-3-one (II), melting at 155 to 157 C., with rotation [1x1 19 (chloroform); optical rotatory dispersion data confirmed the Soc-hydrogen configuration; its nuclear magnetic resonance spectrum supported the proposed structure.

Analysis.Calcd. for C H O C, 79.19; H, 10.76. Found: C, 79.38; H, 11.36.

Following the procedure of Example 3, but substituting 7a,17u-dimethy1 19 nor-17fi-hydroxy-4-androsten-3- one (I) as starting material, yields 7u,17a-dimethyl 19- nor-17fl-hydroxy-5u-androstan-3-one (II).

EXAMPLE 4 A solution of 3 g. of 7a,l7a-dimethyl-17fi-hydroxy-5aandrostan-3-one (II) (from Example 3) in ml. of acetic anhydride and 30 ml. of pyridine is heated at reflux for about 4 hours. After cooling the solution is washed successively with water, dilute acid, dilute base, water, dried over magnesium sulfate, and the solvent removed. The residue is chromatographed through Florisil and crystallized from acetone-Skellysolve B to give 7m,17a-dimethyl17fi-hydroxy-5a-androstan-3-one l7-acetate (II).

Following the procedure of Example 4, but substituting 7u-rnethyl-19-nor-17fi-hydroxy 5a androstan-3-one (II) as starting material, yields 70c,17oc-diII16tl1Yl-19-I1Of-l7fihydroxy-5a-androstan-3-one 17-acetate (II).

In the same manner as in Example 4, the 17fl-hydrocinnamate, cyclopentylpropionate, formate, butyrate, isobutyrate, valerate, isovalerate, hexanoate, octanoate,

- phenylacetate, and other like 17-esters of 7a,17x-dimethyl- 17/3-hydroxy-5a-androstan-3-one (II) are prepared by reaction of their corresponding 175-alcohols with the appropriate halide or acid anhydride.

To approximately 60 ml. of liquid ammonia cooled in a Dry Ice bath, 1 g. of lithium wire was added with stirring. When solution was complete, the cooling bath was removed and a solution of 2 g. of 2a,7a,l7a-trimethyl- 175-hydroxy-4-androsten-3-one (I) in 30 ml. of tetrahydrofuran was added. After stirring for about 15 minutes, 5 g. of ammonium chloride was added, and the excess ammonia evaporated on a warm-water bath. The residue was partitioned between water and methylene chloride, the organic phase separated, washed with cold dilute hydrochloric acid, water, dried and the solvent evaporated. The residue was chromatographed on a 100 g. column of Florisil. The eluate was collected in 200 ml. fractions using a gradient from 2 to 7% acetone in Skellysolve B. Fractions 5 to 13 contained 1.89 g. of crystals which showed no 3-ketone band in infrared absorption spectrum; this material was therefore oxidized by treatment with 1.6 g. of sodium dichromate in 16 ml. of acetic acid at room temperature for 2 hours. The product was isolated by dilution with water and chromatographed as before on a 75 g. column of Florisil. Crystals were obtained from the eluate which showed the presence of a 3-keto substituent. After recrystallization from acetone-Skellysolve B, the product obtained, 2a,7u,17ot-tri- 12 methyl-175-hydr0xy-5a-androstan-3-one (II), melted at 143l44 C. with absorption ,33 3520, 1695, 1166, 1075 cur- Analysis.Calcd. for C H O C, 79.46; H, 10.91. Found: C, 76.16; H, 10.20.

Following the procedure of Example 5, but substituting 2u,7a17ot-trimethyll9-nor-l7fi-hydroxy-4-androsten-3-one (I) as starting material, yields 2a,7a,17u-trimethyl-19- nor-17fl-hydroxy-5u-androstan-3-one (II).

EXAMPLE 6 704,1 7a-dimethyl-3 5,1 7fl-dihydroxyJot-androstane (II) To a solution of 1.1 g. of 7a,17a-dimethyl-175-hydroxy- 5a-androstan-3-one (II) in 23 ml. of methanol and 1 ml. of water, mg. of sodium borohydride wa added while cooling and stirring. After 1.5 hours a few drops of acetic acid was added to destroy the excess borohydride. The reaction mixture was diluted to about 50 ml. with water, the precipitate collected, washed with water and dried. The crude material was recrystallized from aqueous methanol to give 0.67 g. of crude product (II) melting at 209 to 210 C. Another recrystallization gave an analytical sample of 7a,17a-dimethyl-3B,17/8-dihydroxy-5aandrostane (II) melting at 214 to 215 C. and having a rotation [wh of 39 (chloroform).

Analysis.Calcd. for C H O C, 78.69; H, 11.02, Found: C, 78.67; H, 10.92.

Following the procedure of Example 6, but substituting 2a,7a,17 x-trimethyl 17,8 hydroxy-5a-androstan-3-one (II), 201,70,17a-trimethyl-19-nor 17,8 hydroxy 50candrostan-3-one (II), 7a,l7a dimethyl-19-nor-l7B-hydroxy-5a-androstan-3-one (II) and the 17-acylates of the foregoing compounds (II) as starting materials, yields, respectively 2a,7a17a-trimethyl-3fi,17,8-dihydroxy 5aandrostane (II), 20t,70t,170l. trimethyl-l9-nor-3fi,175-dihydroxy-5a-androstane (II), 71x,l7a-dim6thYl-19-nOr-3B, 17fl-dihydroxy-Set-androstane (II) and their corresponding 17-acylates (II).

EXAMPLE 7 (a) 7 0a,] 7a-dimethyl-3a,1 7fl-dihydr0xy-5 a-androstane 1 7- acetate (II) and 7 0a,] 7oc dimethyl-3 [3,1 7fi-dihydroxy- 5 a-androstane 17-acetate (II (a) To a suspension of 3.5 g. of lithium aluminum trit-butoxyhydride in 50 ml. of tetrahydrofuran, 3.5 g. of 7 a, 1 7u-dimethyl- 17 B-hydroxy-S u-androstan-3 -one 17-acetate (II) is added with stirring at 0 C. The suspension is allowed to warm to room temperature during 30 minutes after which dilute hydrochloric acid is added dropwise until all of the excess hydride had been consumed. The solution is diluted further with 50 ml. of water and the tetrahydrofuran removed under reduced pressure. The product is extracted into ether and the combined extracts washed consecutively with water, saturated sodium chloride solution, dried with sodium sulfate and the solution evaporated to dryness under reduced pressure. Thin-layer chromatography on silica gel G (ethyl acetate cyclohexane 1: 1) indicates the presence of both the 3: and 3 3-isomers of the product (II). This material adsorbed onto g. of Florisil in methylene chloride and the column eluted by twenty-five 250 ml. fractions of acetone-Skellysolve B over a gradient of from 0 to 15% acetone. The middle fractions are combined and recrystallized from Skellysolve B to give the 3fl-hydroxy product (II), 70:,17oc-dimethyl-3fl,17,8-di-hydroxy-Sat-androstane 17-acetate.

Following the procedure of Example 7(a), but substitutin g for 7 or, 17 u-dimethyl- 17 B-hydroxy-S u-androstan- 3-one 17-acetate (II) the following representative starting materials:

( 1) 7a,17a-dimethyl-l9-nor-17B-hydroxy-5a androstan- 3-one 17-acetate (II),

(2) 2a,7a,17a-trimethyl-17B hydroxy Set-androstan- 3-one 17-acetate (II) and 13 (3) 206,70,17a-trimethyl-19-nQr-175 hydroxy-5a-androstan-3-one 17-acetate (II),

yields, respectively,

(b) 7 a,] 7 a-dimethy l-3u,1 7 fl-dihydroxyp-androstane 17- acetate (II) and 7 04,1 7 wdimethyl-3 [3,1 7 ,B-dihydroxy-S B- androstane J 7 -acetate (11) (b) To a solution of 1 g. of 7u,17a-dimethyl-17fi-hydroxy-5B-androstan-3-one 17-acetate (II) [obtained by converting 7a,17a-dimethyl-l7fl-hydroxy-5(3-androstan-3- one (II), prepared as in Example 1, to its corresponding 17-acetate (in the manner described in the last paragraph of Example 4)] in 25 ml. of methanol, a solution of 125 mg. of sodium borohydride in 2 ml. of water and ml. of methanol is added. The mixture warms spontaneously and after standing at room temperature for about 20 minutes, excess borohydride is destroyed by addition of a few drops of acetic acid. The reaction mixture is diluted to about 50 ml. with water, extracted with ether, the ether extracts washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The crude solid is recrystallized from acetone-Skellysolve B; recrystallization from the same solvent pair yields pure 7a,17m-dimethyl-3a,17/:l-dihydroxy-Sfi-androstane l7-acetate (II). Chromatography of the mother liquor over a Florisil column yields 7a-methy1-3fl,17,8-dihydroxy-5fiandrostane 17-acetate (11).

Following the procedure of Example 7(b), but substituting for 7a,17a-dimethyl-17B-hydroxy-55-androstan-3- one 17-acetate (II) the following representative starting materials:

( 1) 7a,17a-dimethyl-19-nor-17,6-hydroxy-5B androstan- 3-one 17-acetate (II),

(2) 20,7a,17u-trimethyl17fl-hydroxy-5fi androstan 3- one l7-acetate (II) and (3) 2a,7a,17a-trimethyl-19 nor 17,8-hydroxy-3-one 17- acetate (II),

yields, respectively,

(1) 70:,170v-dit116thYl-19 nor 3a,17/3-dihydroxy-5fl-androstane 17'-acetate (II) and 70,l7oL-di11161ihYl-19-110f- 35,17fl-dihydroxy-5fi-androstane 17-acetate (II),

(2) 20,7a,17a-trimethyl-3a,17fl dihydroxy SB-androstane 1'7-acetate (II) and 2u,7a,17a-trimethyl3,6,l7fldihydroxy-SB-androstane 17-acetate (II), and

(3) 2a,7a,l7a-trimethyl-l9 nor 3a,l7fi dihydroxy-5fiandrostane 17-acetate (II) and 2a,7a,17wtrimethyl-19- nor-35,17 3-dihydroxy-5B-androstane 17-acetate (II).

(c) 7u,17u-dimethyl-3a,1 7B-dihydroxyJot-androstane (II) 100 mg. of 7a,17a-dimethyl-3u,17 8-dihydroxy-5a-androstane 17-acetate (II), obtained according to the procedure of Example 7(a), is dissolved in 4 ml. of 5% potassium hydroxide in methanol, followed by the addition of 4 drops of water. After standing for about hours at room temperature the solution is warmed on a steam bath and diluted to incipient crystallization by the dropwise addition of water. On cooling, a colorless crystalline product (-II) is isolated by filtration and air dried. Recrystallization of this material from alcohol and water gives pure 70,17oc dimethyl-3u,17,8-dihydroxy-5a-androstane (II). Alternatively, the product may be purified by chromatography and crystallization.

Following the procedure of Example 7(c), but substituting for 7a,l 7a-dirnethyl-3a,1'7fl-dihydroxy-5a-androstane 1 4 17-acetate (II) the following representative starting materials:

(1) 7a,17u-dimethyl-l9 nor 3fi,17fl-dihydroxy-5-a-androstane 17-acetate (II),

(2) 7a,17ot-dimethyl-3a,17B-dihydroxy 5,8 androstane l7-acetate II),

(3) 2a,7oc,l7a-Irim6thyl3oc,17 3 dihydroxy Set-androstane 17-acetate (II) and (4) 2m,7ot,17a-trimethyl-19 nor 3,8,17B-dihydroxy-SB- androstane 17-acetate (II),

yields, respectively,

(1) 7a,17a-dimethy1-19 nor 3fi,17fl-dihydroxy-5a-androstane (II),

(2) 7a,17u-dimethyl-3a,17fl-dihydroxy 5B androstane (3) 2a,7a,17 x-trirnethyl 30;,175- dihydroxy-5a-androstane (II) and (4) 2oz,7a,17u-trimethyl-19 nor 3,3,17,8-dihydroxy-5B- androstane (II).

EXAMPLE 8 7 04,1 7a-dimethyl-1 7 B-hydroxy-S wandrostan-3-0ne 3-thioketal To a solution of 2 g. of 7a,17a-dimethyl-17,9-hydroxy- 5a-androstan-3-one (II), (prepared as in Example 3) in 6 ml. of acetic acid cooled to about 10 C., 0.7 ml. of ethanedithiol and 0.7 ml. of boron trifluoride etherate is added. After standing at room temperature for about 20 minutes the reaction mixture is diluted to a volume of about 25 ml. with water and ice. The crystals are collected, washed with water and dried to yield the crude product, which on recrystallization from a mixture of methanol and methylene chloride gives pure 7ot-methyl-17fi-hydroxy-5a-androstan-3-one-3-thioketal.

Following the procedure of Example 8 but substituting the following representative compounds for the starting material employed therein:

1 7 a,17a-dirnethyl-19-n0r-17fl-hydroxy-5 ot-androstan- 3-one (II),

(2) 2a,7a,17a-trimethyl-17B-hydroxy-5a-androstan 3- (II) (obtained in Example 5),

(3 20,7a,17u-trimethyl-19-nor-17p-hydroxy-5u-androstan-3-one (II) (obtained in the paragraph following Example 5),

I(4) 7a,17a-dimethyl-17fl-hydroxy-55-androstan-3 one (5) 20,7a,17rx-trimethyl-17fl-hydroxy-5fl-androstan 3- one (II),

(6) 7a,17a-dimethyl-19-nor-17fi-hydroxy-5B-androstan- 3-one (II) and 7) 2a,7w,17a-trimethyl-19-nor-17B-hydroxy-5/3-androstan-3 one (II), yields, respectively,

1 7oz, 17a-dimethyl-19-n0r-17 8-hydroxy-5a-androstan- 3-one 3-thioketal,

(2) 2a,7u,17a-trimethyl-17fl-hydroxy-5a-androstan 3- one 3-thioketal,

(3 20,7u,17a-trimethyl-19-nor-17B-hydroXy-5a-androstan-3-one 3-thioketal,

(4) 7a,17a-dimethyl-17,B-hydroxy-5fl-androstan 3-one 3-thioketal,

(5 206,7,17a-trimethyl-17p-hydroxy-5 3-androstan 3- one 3-thioketal,

(6) 7a,17a-dimethyl-17-hydroxy-5 3-androstan 3 one 3-thioketal, and

(7) 20,7ot,17a-trimethyl-19-nor-17B-hydroxy-5fi-androstan-3-one (II), yields, respectively,

In the examples relating to 3-thioketals, the specific ketal used is the cyclic 3-(ethylene mercaptole), also named as a cyclic 3-(ethylene dithioketal). For brevity, these are referred to as the 3-thioketal.

I EXAMPLE 9 7a,] 7a-dimethyl-1 75-hydr0xy-5a-androstane (II To a solution of 1 g. of 7a,17u-dimethyl-17fl-hydroxy- SOL-EllldlOSIfll'1-3-OI1B 3-thioketal (obtained in Example 8), 30 ml. of distilled liquid ammonia, ml. of ether and 5 ml. of tetrahydrofuran, 1 g. of sodium metal is added in small pieces. The solution is refluxed for about 15 minutes and the blue color discharged by dropwise addition of absolute ethanol. A rapid stream of nitrogen is passed through the reaction vessel to evaporate the solvents. After removal of most of the ammonia and other solvents, water is added. The resulting precipitate is collected, washed with water, dried and recrystallized from Skellysolve B or chromatographed through a Florisil column to yield 7a,17a-dirnethyl-17/3-hydroxy-5u-androstane (II).

Following the procedure of Example 9 but substituting the following representative compounds for the starting material employed therein:

(1) 7 u,17a-dimethyl-19-nor-17 fi-hydroxy-S a-androstan- 3-one 3-thioketal,

(2) 2a,7a,17u-trimethy1-1713-hydroxy-5a-androstan 3- one 3-thioketal,

(3) ,7a,17a-trimethyl-19-nor-17fi-hydroxy-5a-androstan-3one 3-thioketal,

(4) 70,17a-dimethyl-17fl-hydroxy-5B-androstan 3-one 3-thioketal,

(5) 2a,7a,17 u-trimethyl-17fl-hydroxy-5B-androstan 3- one 3-thioketal,

(6) 7a,17a-dimethyl-17fl-hydroxy-5fl-androstan 3-one 3-thioketal, and

(7) 2a,7m,17u-trimethyl-19-nor-17fl-hydroxy-5fl-androstan-3-one 3-thioketal, yields, respectively,

(1) 7a,17u dimethyl 19 nor-17,8-hydroxy-5a-andro stane (II),

(2) 20,7 04,170 trimethyl 17p hydroxy-h-androstane (3) 2a,7a,17u trimethyl 17/3 hydroxy-5a-androstane (4) 7a,17a-dimethyl-17fl-hydroxy-5B-androstane (II), (5) 201,7 oc,17oc trimethyl 17B hydroxy-Sfi-androstane (6) 7a,17ot-dimethyl-19-nor-17fl-hydroxy-5p-androstane (II), and

(7 2a,7ot,17m-trirnethyl-l9-nor-17,8-hydroxy-5B-androstane (II).

EXAMPLE 10 7a,17a-dimethyl-19-n0r-17f3-hydroxy-4-androsten 3 one 3-thi0ketal (70:,170: dimethyl 19 nor-testosterone 3- thioketal) To a solution of 2 g. of 7a,17a-dimethyl-19-nor-17,8- hydroxy-4-androsten-3-one (I) in 6 ml. of acetic acid cooled to about 10 C., 0.7 ml. of ethaneditbiol and 0.7 ml. of boron trifiuoride etherate is added. After standing at room temperature for about 20 minutes the reaction mixture is diluted to a volume of about ml. with water and ice. The crystals are collected, washed with water and dried to yield the product, which is recrystallized from a mixture of methanol and methylene chloride or other inert solvent to give 2.3 g. of 7a,17a-dimethyl-l9-nor-l7i3- hydroxy-4-androsten-3-one 3-thioketal.

Following the procedure of Example 10 but substituting the following compounds for the starting material employed therein:

(1) 7a,17a-dimethyl-17p-hydroxy-4-androsten-3-one (I), (2) 20,7a,17a-trimethyl-17,6-hydroxy-4-androsten 3 one (I) and 3-one (I), yields, respectively,

(1) 7a,17a-dimethyl-17B-hydroxy-4-androsten 3 one 3- thioketal,

1.6 (2) 2a,7a,17ot-trimethyl-175-hydroxy-4-androsten 3 one 3-thioketal, and (3 2u,7a,17a-trimethyl-19-nor-17,6-hydroxy-4-androsten- 3-0ne 3-thioketal.

EXAMPLE 1 1 To a solution of 1 g. of 7a,17u-dimethyl-19-nor-175- hydroxy-4-androsten-3-one 3-thioketal, 30 ml. of distilled liquid ammonia, 15 ml. of ether and 5 ml. of tetrahydrofuran, 1 g. of sodium metal is added in small pieces. The steroid goes into solution rapidly as the sodium dissolves. The solution is refluxed for about 15 minutes and the blue color is discharged by dropwise addition of absolute ethanol. A fast stream of nitrogen is passed through to aid in evaporating the solvents. After nearly all of the ammonia and other solvents are removed, water is added. The resulting precipitate is collected, washed with water, dried and recrystallization from Skellysolve B or chromatographed through a Florisil column to yield 70:,1704- dimethyl-19-nor-17fl-hydroxy-4-androstene (II).

Following the procedure of Example 11 but substituting the following compounds for the starting material em ployed therein:

( 1 7 a, 17 a-dirnethyl- 1713-hydroxy-4-androsten-3 -one 3-thioketal,

(2) 206,7 0:, 17 tx-trimethyl- 17p-hydroxy-4-androsten-3-one 3-thioketal and (3 20,7a,17a-trimethyl-19-nor-17B-hydroxy-4-androsten- 3-one 3-thioketal,

yields, respectively,

( 1) 7a,17a-dimethyl-17B-hydroxy-4-androstene, (2) 2a,7a,17a-trimethyl-17B-hydroxy-4-androstene and (3 202,7 a, 17a-trimethyl-19-nor- 17 ,B-hydroxy-4- androstene.

EXAMPLE 12 A suspension containing 1 g. of 7a,17a-dimethyl-19- nor-17l3-hydroxy-4-androstene (obtained in Example 11) and 0.2 g. of 5% palladium-on-charcoal in 200 ml. of alcohol is reacted with hydrogen until 1 mole equivalent of hydrogen is consumed. The catalyst is filtered OE and the filtrate concentrated to dryness. The residue is purified by chromatography employing a column of Flori sil to give 7a,17ot-dimethyl-19-nor-17B-hydroxy-5fi-androstane (II).

Following the procedure of Example 12, but substituting Adams (platinum dioxide) catalyst for 5% palladiumon-charcoal also yields 7a,17a-dimethyl-19-nor-17B-hydroxy-SB-androstane (II).

Following the procedure of Example 12 but substituting the following representative compounds for the starting material employed therein:

( 1) 7a,17a-dimethyl-17B-hydroxy-4-androstene, (2) 2a,7ot,17u-trimethyl-17fi-hydroxy-4-androstene and (3 20,7oc,l7oc-t1iII16thYl-l9-1'lOI-l7B-hydrOXy-4- androstene,

yields, respectively, (1) 7 a,17ot-dimethyl-17fi-hydroxy-5 p androstane (II), (2) 2a,7a,17a-trimethyl-17,8-hydroxy-5B-androstane (II) and (3 2u,7a,17a-trimethyl-19-nor-17B-hydroxy-5flandrostane (II).

EXAMPLE 13 704,] 7a-dimethyl-3a,17B-dihydroxy-5,8-andr0stane (II To a solution of 1 g. of 7a,17oc-dimethyl-17B-hydroxy- 5/3-androstan-3-one (II) (prepared as in Example 1) in ml. of tetrahydrofuran, 1.5. g. of lithium aluminum tri-t-but y ydride is added at about 0 C. with stirring.

(1) 7 a,17a-dimethy1-19-nor-17fl-hydroxy-5fi-androstan- 3-one (II),

(2) 2a,7a,17a-trimethyl-17,8-hydroxy-5fi-androstan- 3-one (II) and (3) 2a,7u,17a-trimethyl-19-nor-17fi-hydroxy-5flandrostan-3-one (II),

yields, respectively,

(1) 7a, 17a-dimethyl-19-nor-3a,17fi-dihydroxy-5 8- androstane (II), (2) 2u,7a, 17a-trimethyl-3a, 17fi-dihydroxy-Spandrostane (II) and (3) 2a,7a,17a-trimethyl-19-nor-3a,17,3-dihydroxy-5fiandrostane (II).

EXAMPLE 14 4,7 a,] 7 a-trimethy [-1 7 fi-hydmxy-4 -andr0sten-3-0ne 1 7 acetate (4,7a,17a-trimethyltestoster0ne 17-acetate) (II) To a flask containing a mixture of 4.4 m1. of thiophenol, 2.6 ml. of 38% aqueous formaldehyde, 2. 6 ml. of trimethylamine and 9 ml. of ethanol, 5 g. of 7a,17u-dimethyl 17B hydroxy 4 androsten 3 one (7u,17 xdimenthyltestosterone) (I) is added and the mixture is refluxed for 6 days. The reaction mixture is cooled, poured into 200 ml. of aqueous potassium hydroxide and the steroid extracted with methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated to dryness by vacuum distillation over a steam bath. This material, (7a,17a-dimethyl-17;8-hydroxy- 4-androsten-3-one 4-methylthiophenol) (I'), is dissolved in 50 ml. of pyridine and acetylated with 20 ml. of acetic anhydride by warming to about 80 C. for about 16 hours. The mixture is poured into ice water and allowed to stand for about 40 minutes to hydrolyze the excess acetic anhydride. The product (the 17-acetate of 7a,17a-dimethyl- 17B hydroxy 4 androsten 3 one 4 methylthiophenol) (1) is extracted with methylene chloride, the extract washed successively with cold dilute hydrocloric acid to remove the pyridine, with aqueous sodium bicarbonate, finally water and dried over anhydrous sodium sulfate. The dried extract is concentrated and then dissolved in about 60 ml. of acetone. Approximately 50 ml. of Raney nickel sludge is washed by decantation three times with 200 ml. portions of acetone. The sludge is then suspended in 200 ml. of acetone and refluxed with eflicient stirring for about 60 minutes in a nitrogen atmosphere. The 17- acetate of the 4-methylthiophenol steroid (1") in acetone solution is added to the acetone suspension of Raney nickel and the mixture stirred and refluxed for about 4 hours. The Raney nickel is filtered from the acetone solution through a half-inch bed of Celite (diatomaceous earth). The flask is rinsed and the residue washed with 100 ml. of hot ethyl alcohol. The residue is finally washed with 50 ml. of deionized water and discarded. The filtrate is concentrated to dryness by vacuum distillation. The total crude product (II) is dissolved in 75 ml. of methylene chloride and chromatographed over a 280 g. column of Florisil. The column is developed with 100 ml. portions of acetone in Skellysolve B. The major portion of the eluate is crystallized from Skellysolve B to give the desired product, 4,7a,17a-trimethyl17,8-hydroxy-4-androsten-3-one 17-acetate (II).

Following the procedure of Example 14, but substituting the other compounds embraced by Formula I of the flow-sheet on page 2, above, as starting materials, yields the corresponding compounds of Formula H thereof. Thus,

1 8 replacing 7a, l7u-dimethyl-17,8-hydroxy-4-androsten-3-one (I) by:

(1 7a,17tx-dimethyl-19-nor-17;3-hydroxy-4-androsten- 3-one,

(2) 2a,7a,l7a-trimethyl-17/i-hydroxy-4-androsten- 3-one (I),

(3) 2a,7tx,17ot-triemthyl-19-nor-17fi-hydroxy-4- androsten-3-one (I),

(4) 7a,17a-dimethyl-3a,17 3 dihydroxy-4-androstene (I),

(5) 7m,17a-dimehyl-19-nor-3,8-17B-dihydroxy-4- androstene (I),

(6) 2a,7 a, 17 a-trimethyI-S a,17/3-dihydroxy4- androstene (I) and (7 20,7a,17a-trimethyl-19-nor-3fl,17fi-dihydroxy-4- androstene (1),

yields, respectively,

(1) 4,7a,17a-trimethyl-17/8-hydroxy-l9-nor-l7fihydroxy-4-androsten-3-one 17-acetate (II),

(2) 2a,4,7a,17a-tetramethyl-17fl-hydroxy-4-androsten- 3-one 17-acetate (II),

(3 2a,4,7a, l7a-tetramethyl-19-nor-175-hydroxy-4- androsten-S-one 17-acetate (II),

(4) 4,70, 17a-trimethyl- 3 0c, 17,8-dihydroxy-4-androstene 3,17-diacetate (II),

( 5) 4,711,17a-trimethyl-19-nor-3,8, l 7/3-dilhydroxy-4- androstene 3,17-diacetate (II),

(6) 2oz,4,7a,17m-tetramethyl-3u,17/3-dihydroxy-4- androstene 3,17-diacetate (II) and (7) 2u4,7a,17a-tetramethyl-19-nor-3fi,17,8-dihydroxy-4- androstene 3,17-diacetate (II).

Following the procedure of Example 7(a) but substituting the products prepared in Example 14 and those of the immediately preceding paragraph, converts the 17- aceta-tes and 3,17-diacetates therein to the corresponding 3-hydroxy and 3,l7-dihydroxy compounds.

EXAMPLE 15 4,7a,17u-trimethyl-17 B-hydroxy-4-androsten-3-one (4, 7a,] 7 ot-trimethyltestosterone) (II) To 600 mg. of 4,7u,17u-trimethyl-l7/3-hydroxy-4-androsten-3-one 17-acetate (II) dissolved in 50 ml. of ethanol, mg. of potassium hydroxide is added. The mixture is swirled until the base dissolves and is allowed to stand at room temperature for about 20 hours. The mixture is then made barely acidic with dilute acetic and the major portion of the ethanol removed by vacuum distillation. The product separates from the mixture and is collected by filtration, washed with deionized water and dried under vacuum at 40 C. or is extracted with methylene chloride, washed with water until neutral, dried over sodium sulfate. The solvent is removed and the residue chromatographed and recrystallized to give 4,70,- 17a-trimet'hyl-17fi-hydroxy-4-androsten-3-one (II).

Following the procedure of Example 15, but substituting for 4,70,l7u-trimethyl-17fi hyd-roxy-4-androsten-3-one 17-acetate '(II), the following representative starting materials:

( 1) 4,7a,17u-trimethyl-17}8-hydroxy-4-androsten- 3-o11e 17-acetate (II),

(2) 4,7u,17a-trimethyl-l7fl-hydroxy-19-nor-17B- hydroxy-4-androsten-3-one 17-acetate (II),

(3) 2a,4,7a,17ot-tetramethyl-17B-hydroxy-4-androsten- 3-one l7-acetate (II),

(4) 2a,4,7u,17a-tetramethyl-19-nor-l7fi-i1ydroxy- 4-androsten-3-one 17-acetate (II),

(5) 4,7,17u-trimethyl-3fl,17p dihydroxy-4-androstene 3,17-diacetate (II),

( 6) 4,711,17a-trimethyl-19-nor-3a,17,8-dihydroxy- 4-androstene 3,17-diacetate (II),

( 7) 2oz,4,7oc, 1 7a-tetramethyl-3fi, 17,8-dihydroxy- 4-androstene 3,17-diacetate (II) and 1 i) (8) 2m,4,7a,17ot-tetramethyl-19-nor-3/i,17p-dihydroxy- 4-andro'stene 3,17-diacetate (II),

yields, respectively,

( 1) 4,7 17a-trimethyl- 17fi-hydroxy-4-androsten- 3-one (II),

(2) 4,70,17a-trimethyl-l7B-hydroxy-19-nor-17B- hydroxy-4-androsten-3one (II),

(3) 2a,4,7a,17a-te-tramethy1-17,B-hydroxy- 4-androsten-3-one (II),

(4) 206,4,70L, 17 ot-tetramethyl-l 9-nor-17B-hydroxy- 4-androsten-3-one (II),

(5) 4,7ot,17a-trimethyl-3B,l7p-dihydroxy-4- and-rostene (II),

(6) 4,7a,17a-trimethyl-19-nor-3a,17B-dihydroxy- 4-androstene (II),

(7) 2u,4,7ot,17a-tetramethyl-3/3,l7fl-dihydroxy- 4-androstene (II), and

(8) 204,4,7ot,l7ix-tetramethyl-19-nor-3,8,17,8-dihydroxy- 4-androstene (II).

EXAMPLE 16 4 a] 00,] 7a-trimethyl-1 7 fl-hydroxy-Sfi-and restart-3 -0ne (II A solution of 1 g. of 4,7a,l7ot-trimethyl-l7B-hydroxy- 4-androsten-3-one (4,711,17a-trimethyltestosterone) (11) (prepared as in Example 15) in 250 ml. of 95% ethyl alcohol is reacted with hydrogen using 5% palladium on charcoal catalyst until 1 mole equivalent of hydrogen is absorbed. The catalyst is removed by filtration through a bed of Celite (diatomaceous earth). The filtrate is concentrated to dryness, chromatographe-d and recrystallized from a mixture of acetone and Skellysolve B to give 4a,- 70c, 17a-trirnethyl- 17 fi-hydroxy-Sfi-androstan-3-one (II).

Following the procedure of Example 16 but substituting for 4,7a,l7ot-trimethyl-17fl-hydroxy-4-androsten-3-one (II), the following representative starting materials:

( 1) 4,711,17a-trimethyl-19-nor-17fi-hydroxy- 4-androsten-3-one (II) and (2) 4,701,l7a-trimethyl-19-nor-17;3-hydroxy- 4-androsten-3-one 17-acetate (11),

yields, respectively,

( 1 404,704,17u-trimethyl-19-nor-17B-hy'droxy-5fiandrostan-3-one (II) and (2 40,7a,l7a-trimethyl-19-nor-17fl-hydroxy-5flandrostan-3-one 17-acetate (II).

EXAMPLE 17 2u,4,7a,17a-tetramethyl-1 7B-hydroxy-4- andr0sten-3-one (II) (a) To a solution of 50' g. of 4,7a,17xtrimethyl-17B- hydroxy-4-androsten-3-one (4,700,17oz trimethyltestosterone) (II) (prepared as in Example 15) in 750 ml. of tbutyl alcohol, warmed to 55 C. in a nitrogen atmosphere, 50 ml. of ethyl oxalate and 65 ml. of 25% sodium methoxide solution is added with stirring. Stirring is continued for about 20 minutes after which 750 ml. of ether is added. The mixture is filtered and the solid of crude yellow glyoxalate dried in a vacuum oven. A mixture of the crude glyoxalate, potassium carbonate, methyl iodide and acetone is stirred and heated under reflux for about 24 hours. Approximately, a third of the liquid is distilled 01f and the remaining mixture filtered. The filter cake is washed with acetone and the combined mixture filtered. The cake is washed with additional acetone and the combined filtrate evaporated at reduced pressure to an amber gum which is dissolved in methanol purged with nitrogen and treated with 25% sodium methoxide solution. After about 2 hours, saturated sodium chloride solution is added, and the mixture extracted with methylene chloride. The extract is dried and the solvent evaporated. The crude gummy product is purified via chromatography on a column of Florisil. A mixture composed of a minor proportion of acetone and the remainder Skellysolve B eluted light colored crystals, which on recrystallization from acetone-Skellysolve B yields the desired product, pure 2m,4,7a,17x-tetramethyl-17,8-hydroxy-4-androsten-3- one (II).

Following the procedure of (a) of Example 17, but substituting for the starting steroid 4,7u,l7a-trimethyl- 17B-hydroxy-4-androsten-3-one (II), the following representative starting materials:

( 1) 4,7'u,17u-t1'imethyl-19-nor-17fl-hydroxy- 4-androsten-3-one (II) and (2) 4,7 04, 17 a-trimethyl-19-nor-17fi-hy-droxy- 4-androsten-3-one 17-acetate (II),

yields, respectively,

(1) 2a,4,7a,17a-tetramethyl-19-nor-17fl-hydroxy- 4-androsten-3-one (II) and (2) 2a,4,7a,17a-tetramethyl-19-nor-17fi-hydroxy- 4-androsten-3-one 17-acetate (II).

(19) Following the procedure of Example 16, but substituting 2a,4,7a,17a-tetramethyl-17,8 hydroxy-4-androsten- 4-0ne (II) and its corresponding l9-nor derivative (prepared as in the preceding two paragraphs) as starting materials, yields 2a,4u,7u,17a-tetramethyl-17B-hy'droxy- 4-andros-ten-3-one (II) and its l9-nor counterpart (II), respectively.

EXAMPLE 18 4a,7ot,1 7a-trimethyl-1 7,13-hydroxy-5o-andr0stan 3-0n e (II) To about 1.2 1. of liquid ammonia, 0.8 g. of lithium wire cut in small pieces is added. After the lithium dissolves, 10 g. of 4,70,17ot-trimethy1-l7fi-hydroxy-4eandrosten-3-one (II) in 200 ml. of tetrahydrofuran (purified by passage through an aluminum oxide column) is added in a slow stream at reflux. The solution is refluxed for about 15 minutes, then 15 g. of solid ammonium chloride is added in small portions. The ammonia produced is rapidly evaporated on a steam bath. Water is added and the product extracted with ether. The ether extract is washed successively with water, dilute hydrochloric acid, Water and brine, then dried over magnesium sulfate, filtered and concentrated to dryness. The amorphous solid is dissolved in methylene chloride and the solution poured onto a 250 g. Florisil column packed wet with Skellysolve V and eluted (employing 400 m1. fractions) by gradient elution between 5 l. of a mixture comprising 2% acetone and 98% Skellysolve B and 5 l. of a mixture of 12% acetone and 88% Skellysolve B to give the desired material. Recrystallization of material from acetone- Skellysolve B provided the desired pure product, 4a,7a, 17a-trimethyl-17/3-hydroxy-5a-androstan-3-one (II).

Following the procedure of Example 18, but substituting 4,7oc,l7a trimethyl-19-nor-17fl-hydroxy-4-androsten- 3-one (II) as starting material yields 4a,7a,17a-trimethyl 19-nor-17B-hydroxy-5u-androstan-3-one (II).

EXAMPLE l9 211,4 04,70 1 7a,tetram ethyl-] 7B-hydroxy-5a-androstan- 3-0ne (II To approximately 60 ml. of liquid ammonia cooled in a Dry-Ice bath, 1 g. of lithium wire is added With stirring. When solution is complete, the cooling bath is removed and a solution of 2 g. of 2a,4a,7a,17a-tetramethyl-l7B-hydroxy-4-androsten-3-one (II) in 30 ml. of tetrahydrofuran is added. After stirring for about 15 minutes, 5 g. of ammonium chloride is added, and the excess ammonia evaporated on a warm-water bath. The residue is partitioned between water and methylene chloride, the organic phase is separated, washed with cold dilute hydrochloric acid, Water, dried and the solvent evaporated. The residue is chromatographed on a 100 g. column of Florisil. The eluate is collected in 200 ml. fractions using a gradient from 2 to 7% acetone in Skellysolve B. Some fractions contained residues which showed no 3-ketone band in infrared absorption spectrum; this material is EXAMPLE 2O 4a,7a,17u-trim ethyZ-3fl,17,8-dihydr0xy-5aandrostane (II) To a solution of 1.1 g. of 40,7a,17u-trimethy1-17p-hydroxy-a-androstan-3-one (II) in 23 ml. of methanol and 1 ml. of water, 150 mg. of sodium borohydride is added while cooling and stirring. After 1.5 hours a few drops of acetic acid is added to destroy the excess borohydride. The reaction mixture is diluted to about 50 ml. with water, the precipitate collected, washed with water and dried. The crude material is recrystallized from aqueous methanol to give 404,7a,l7a-trimethyl-3/3,17fi-dihydroxy- Set-androstane (II).

Following the procedure of Example 20, but substituting 2a,4a,7a,17a-tetramethyl 17,6 hydroxy-5a-androstan-S-one (II), 2a,4a,7a,17u-tetrarnetl1yl-19-nor-l7phydroxy-5a-androstan (II), 40,7u,17a-trimethyl-19-nor- 17B-hydroxy-5u-androstan-3-one (II), and the 17-acylates of the foregoing compounds (II) as starting materials, yields, respectively, 2a,4u,7a,17a-tetramethyl-3B,

17B-dihydr0xy-5a-androstane (II), 2a,4u,7oc,17cc-t6tra methyl-19-nor-3p,17fi-dihydroxy-5rat-androstane (II), 411, 711,170; trimethyl-19-nor-3B,17,8-dihydroxy 5a androstane (II) and their corresponding 17-acylates (II).

EXAMPLE 21 (a) 4 ut,7oz,1 7 a-trimethyl-3 (1,1 7 fi-ziihydroxy-S rat-androstane 17-acetate (II and 4 a,7oc,1 7 a-trimethyl-j [3,1 7 ,B-dihydroxy-Sa-androstane 17-acetate (II) (a) To a suspension of 1.5 g. of sodium borohydride in 50 ml. of tetrahydrofuran, 3.5 g. of 4a,7oc,17ot-tTimethyl-17/i-hydroxy-5u-androstan-3-one 17-acetate (II) is added with stirring at 0 C. The suspension is allowed to warm to room temperature during 30 minutes after which dilute hydrochloric acid is added dropwise until all of the excess hydride is consumed. The solution is diluted further with 50 ml. of water and the tetrahydrofuran removed under reduced pressure. The product is extracted into ether and the combined extracts washed consecutively with water, saturated sodium chloride solution, dried with sodium sulfate, and the solution evaporated to dryness under reduced pressure. Thin-layer chromatography on silica gel G (ethyl acetate-cyclohexane 1:1) indicates the presence of both the 3aand 3,9-

isomers of the product (II'). This material is adsorbed onto 175 g. of Florisil in methylene chloride and the column eluated with acetone-Skellysolve B over a gradient of from 0 to acetone. The fractions containing the minor isomer are combined and recrystallized from acetone-Skellysolve B to give 4a,7a,17u-trimethyl-3u,17fldihydroXy-Sa-androStane 17-acetate (II).

Following the procedure of Example 21 (a), but substituting for 4u,7a,17a-trimethyl-17fl-hydroxy-5a-androstan-3-one 17-acetate (II) the following representative starting materials:

( 1) 4a,7u,17a-trimethyl-17/3-hydroxy-5a-androstan-3- one 17-acetate (II'),

(2) 2a,4a,7a17a-tetramethyl-17fl-hydroxy-5oc-androstan- 3-one 17-acetate (II) and I 22 (3) 20,4a,7a,17a-tetramethyl-19-nor-17fi-hydroxy-5'ozandrostan-3-one 17-acetate (II),

yields, respectively,

( 1) 4a,7a,17a-trimethyl-19-nor-3a,17 3-dihydroxy-5a-androstane 17-acetate (II) and 4a,7u,17a-trimethyl-19- nor-36,17 3-dihydroxy-5rat-androstane 17-acetate (II),

(2) 2n,4a,7a,l7a-tetramethyl-3a,l7fl-dihydroxy-5a-androsane 17-acetate (II) and 2u,4a,7u,17a-tetramethyl-3p, 17,6-dihydroxy-5rat-androstane 17-acetate (II) and 3) 2u,4 x,7a,17a-tetramethyl-3 a,17/3-dihydroxy-5u-androstane 17-acetate (II) and 2a,4a,7u,17u-tetramethyl-3 3, 17fl-dihydroxy-5a-androstane 17-acetate (II).

(b) To a solution of 1 g. of 4a,7u,17u-trimethy1-17B- hydroxy-5fl-androstan-3-one 17-acetate (11) [obtained by converting 4oz,7a,l7a-trimethyl 17,6 hydroxy-Sfi-androstan-3-one (II), prepared as in Example 16, to its corresponding l7-acetate (in the manner described in the last paragraph of Example 4)] in 25 ml. of methanol, a solution of 125 mg. of sodium borohydride in 2 ml. of water and 10 ml. of methanol is added. The mixture warms spontaneously and after standing at room temperature for about 20 minutes, excess borohydride is destroyed by addition of a few drops of acetic acid. The reaction mixture is diluted to about 50 ml. with water, extracted with ether, the ether extracts washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The crude solid is recrystallized from acetone-Skellysolve B; recrystallization from the same solvent pair yields pure 4a,7u,l7u-trimethyl-3a,17,B-dihydroxy-Sfl-androstane 17-acetate (II). Chromatography of the mother liquor over a Florisil column yields 4u,7a,17 x-trimethyl 3,8,17,6 dihydroxy 5,8 androstane 17-acetate (II).

Following the procedure of Example: 21(b), but substituting for 4a,7a,17a-trimethyl-17/3'hydroxy-5fl-androstan-3-one 17-acetate (II) the following representative starting materials:

( 1) 4o 7,17a-trimethyl-19-nor-17,8-hydroxy-5fi-androstan-S-one 17 acetate (II),

(2) 2a,4a,7a,17a-tetramethyl-17fl-hyclroxy-5l3 androstan- 3-one 17-acetate (II) and (3) 2a,4u,7oz,17a-tetramethyl-19-nor-17fl-hydroxy-3-one 17-acetate (II),

yields, respectively,

(1 4a,7oz,17a-trimethyl-19-nor-3a,17,8-dihydroxy-5B- androstane 17-acetate (II) and 4a,7a,17a-trimethyl-19- nor-3,8,17/3-dihydroxy-5B-androstane 17-acetate (II),

(2) 2a,4a,7a,17a-tetrametl1yl-3u,l7fi-dihydroxy-5fl-androstane 17-acetate (II) and 2a,4a,7a,17a-tetramethyl- 3/3,l7/9-dihydroxy-5fi-androstane 17-acetate (II), and

( 3) 2a,4a,7a,17a-tetramethyl-19-nor-3a,Nit-dihydroxy- Sfl-androstane l7-acetate (II) and 2m,4u,7 x,17a-tetramethyl-19-nor-3,8,17fl-dihydroxy-5p-androstane 17-acetate (II).

(c) 4 oc,7ot,1 7a-trimethyl-3 (1,1 7 ;8-dihydr0xy-5aandrostane (II) 1 (c) mg. of 4a,7u,l7ot-trimethyl-3a,l7,8-dihydroxy- Soeandrostane 17-acetate (II), obtained according to the procedure of Example 21(a), is dissolved in 4 ml. of 5% potassium hydroxide in methanol, followed by the addition of 4 drops of water. After standing for about 15 hours at room temperature the solution :is warmed on a steam bath and diluted to incipient crystallization by the dropwise addition of water. On cooling, a colorless crystalline product (II) is isolated by filtration and air dried. Recrystallization of this material from alcohol and water gives pure 4a,7a,17a-trirnethyl-3a:,Hit-dihydroxy- Set-androstane (II).

23 Following the procedure of Example 21(c), but substituting for 40,7oc,l'loutrimethyl-F:0:,17/3-dihYdIOXY-5oc-3f1- drostane 17-acetate (II) the following representative starting materials:

( 1) 40,7oc, l7ot-trimethyl-l9-nor-3f3,17B-dihydroxy-5aandrostane 17-acetate (II),

(2) 2u,4ot,7a,l7a-tetramethyl-3a,17B-dihydroxy-5aandrostane 17-acetate (II) and (3) 2a,4a,7a,17a-tetramethyl-l 9-nor-3fi-l7B-dihydroxy- SB-androstane 17-acetate (11),

yields, respectively,

(1) 4a,7a,l7a-trimethyl-19-nor-3B,17fi-dihydroxy-5otandrostane (II),

(2 2a,4a,7a,17a-tetramethyl-3 a, 17 fi-dihydroxy-S uandrostane (II), and

(3) 2oc,4oc,7 04,17 a-tetramethyl- 19-nor-3 B, 17 fi-dihydroxy- SB-androstane (II).

EXAMPLE 22 4,7a,1 7a-trimethyl-1 9-n0r-17B-hydr0xy-4-androsten-3-0ne 3-thioketal (4,7u,1 71x, trimethyl-I 9-n0rlest0szer0ne-3- thioketal To a solution of 2 g. of 4,7a,17a-trimethyl-l9-nor-l7B- hydroxy-4-androsten-3-one (II) in 6 ml. of acetic acid cooled to about C., 0.7 ml. of ethanedithiol and 0.7 m1. of borontrifluoride etherate is added. After standing at room temperature for about 20 minutes to 4 hours the reaction mixture is diluted to a volume of about ml. with water and ice. The crystals are collected, washed with water and dried to yield the product, which is recrystallized from a mixture of methanol and methylene chloride to give 4,7,l7a-trimethyl-19-nor-17/8-hydroxy-4-androsten-3-one 3-thioketal.

Following the procedure of Example 22 but substituting the following compounds for the starting material employed therein:

(1) 4,70,l7a-trimethyl-17fi-hydroxy-4-androsten-3-one (2) 2u,4,7a,17a-tetramethyl-17Bhydroxy-4-androsten-3- one (II) and (3 204,4,701,17a-tetramethyl-19-nor-17B-hydroxy-4-androsten-3-one (11),

yields respectively,

(1 4,7 a,17u-trimethyl-17B-hydroxy-4-androsten-3-one 3-thioketal,

(2) 2a,4,7u,17x-tetramethyl-17fi-hydroxy-4-androsten-3- one 3-thioketal and (3) 2u,4,7u,17a-tetramethyl-19-nor-l7B-hydroxy-4-androsten-3-one 3-thioketal.

EXAMPLE 23 4,7u,17a-trimethyl-19-n0r-1 7fl-hydroxy-4-androstene (4,7a,17ot-trimethylester-4-en-17fl-0l) (II) To a solution of 1 g. of 4,704,l7a-trimethyl-l9-nor- 17fi-hydroxy-4-androsten-3-one 3-thioketal, ml. of distilled liquid ammonia, 15 ml. of ether and 5 ml. of tetrahydrofuran, 1 g. of sodium metal is added in small pieces. The steroid goes into solution rapidly as the sodium dissolves. The solution is refluxed for about 15 minutes and the blue color is discharged by dropwise addition of absolute ethanol. A fast stream of nitrogen is passed through to aid in evaporating the solvents. After nearly all of the ammonia and other solvents are removed, water is added. The resulting precipitate is collected, washed with water, dried and recrystallized from Skellysolve B to yield 24' 4,700, l7a-trimethyl-l 9-norl7fi-hydroxy-4-androstene (II). Following the procedure of Example 23 but omitting tetrahydrofuran also yields 4,70,17a-trirnethy1-l9-nor-17B- hydroxy-4-androstene (II).

Following the procedure of Example 23 but substituting the following compounds for the startin material employed therein:

( 1 4,7a,17a-trimethyl-17B-hydroxy-4-androsten-3-one 3-thi-oketal,

(2) 2a,4,7a,17a-tetramethyl-17 8-hydroxy-4-androsten-3- one 3-thioketal and (3 2a,4,7a,17a-tetramethyl-19-nor-17fl-hydroxy-4-androsten-3-one 3-thi0ketal,

yields, respectively,

(1) 4,7ix-dimethyl-17,8-hydroxy-4-androstene (II),

(2) 2a,4,7o,l7a-tetramethyl-1718-hydroxy-4-androstene (II) and (3 2a,4,7a,17a-tetramethyl-19-nor-17,8-hydroxy-4-androstene (II).

Following the procedure of Example 23 and the two paragraphs immediately preceding the present one but substituting as starting materials for the 17B-hydroxy compounds disclosed therein, a corresponding 17-acy1ate thereof, e.g., a 17-acetate or one of those listed at the end of Example 4, yields the corresponding 3-thioketal counterpart of the aforesaid acylate.

EXAMPLE 24 To a solution of 2 g. of 4a,7a,17a-trimethyl-17fl-hydroxy-5a-androstan-3-one (II) (prepared as in Example 19) in 6 ml. of acetic acid cooled to about 10 C., 0.7 m1. of ethanedithiol and 0.7 ml. of borontrifluoride etherate is added. After standing at room temperature for about 20 minutes the reaction mixture is diluted to a volume of about 25 ml. with water and ice. The crystals are collected, washed with water and dried to yield the crude product, which on recrystallization from a mixture of methanol and methylene chloride gives pure 4oz,7oc,l7atrimethyl-17p-hydroxy-5a-androstan-S-one 3-thioketal.

Following the procedure of Example 24 but substituting the following representative compound for the starting material employed therein:

(1 2a,4m,7a,17a-tetramethyl-17B-hydroxy-5 a-androstan- 3-one (II),

( 2) 400,7 0:, 17u-trimethy1- 19-nor-17,13-hydroxy-5a-androstan-3-one (II),

(3 2a,4u,7 a-trimethyll9-nor- 17 fi-hydroxy-S oc-andIO- stan-3-one (II),

(4) 2a,4a,7a,17a-tetramethyl-19-nor-17B-hydroxy-5aandrostan-3-one (II),

(5) 40570:, 1 7 a-trimethy1-17 fi-hydroxy-S ,B-androstan-S- one (II),

(6) 2a,4a,7a-trimethyl-17,8-hydroxy-5p-androstan-3-one (7) 2a,4a,7a,17a-tetramethyl-17B-hydroxy-5fi-androstam 3-one (II),

(8) 4a,7a, l 7a-trimethyll9-norl7fi-hydroxy-5fl-androstan-3-one (II),

(9 2a,4oc,7a-trimethyl-19-nor-17,8-hydroxy-5p-androstan-3-one (II) and (10) 2a,4a,7a,17a-tetramethyl-19-nor-17B-hydroxy-5 S- androstan-3-one (II),

yields, respectively,

(1 2a,4ot,7 oz, 17 a-tetramethyl- 17 fl-hydroxy-S a-androstan- 3-one 3-thioketal,

(2) 404,70, 17a-trimethyl-19-nor-17,8-hydroxy-5 a-androstan-3-one 3-thioketal,

(3 2a,4a,7 u-trimethyl- 19-nor- 17 fi-hydroxy-5 ot-androstan-3-one 3-thioketal,

I (7) 2a,4ot,7u,17a-tetramethyl-17p-hydroxy-5fi-androstan- 3-one 3-thioketal,

(8) 4a,7a,17a-trimethyl-175-hydroxy-5 3-androstan-3-one 3-thioketal,

(9) 2a,4a,7a-trimethyl-19-nor-l7B-hydroxy-5fl-androstan-3-one 3-thioketal, and

(10) 2u,4a,7u,l7a-tetramethyl-19-nor-17/3-hydroxy-51S- androstan-B-one 3-thioketal.

EXAMPLE 25 4 a,7 L1,] 7 a-trimethyl-l 7 13-hydroxy-5 oc-llndlO-SICZHE l I To a solution of 1 g. of 4a,7a,17a-trimethyl-17fl-hydroxy-a-androstan-3-one 3-thioketal (obtained in Example 3), 30 ml. of distilled liquid ammonia, 15 ml. of ether and 5 ml. of tetrahydrofuran, 1 g. of sodium metal is added in small pieces. The solution is refluxed for about 15 minutes and the blue color discharged by dropwise addition of absolute ethanol. A rapid stream of nitrogen is passed through the reaction vessel to evaporate the solvents. After removal of most of the ammonia and other solvents, water is added. The resulting precipitate is collected, washed with water, dried and recrystallized from acetone Skellysolve B to yield 4a,7a,17a-trimethyl- 17fi-hydroxy-5a-androstane (II). Alternatively, purification can be done by chromatography through Florisil followed by recrystallization from acetone Skellysolve B.

Following the procedure of Example 25 but substituting the following representative compounds for the starting material employed therein:

( 1 2a,4a,7oz, l 7a-tetramethyl-17/3-hydroxy-5u-androstan- 3-one 3-thioketal,

(2) 40,7a,l7a-trimethyl-19-nor-l7fi-hydroxy-5a-androstan-3-one 3-thioketal,

(4) 4a,7a,17a-trimethyl-17li-hydroxy-5B-androstan-3- one 3-thioketal,

(5) 2a,4a,7u,17a-tetramethyl-17/3-hydroxy-5/3-androstan- 3-one 3-thioketal,

(6) 411,711,17a-trimethyl-17,8-hydroxy-5fi-androstan-3-one S-thioketal,

(7) 2ot,4a,7a,17u-tetramethyl-19-nor-17p-hydroxy-5aandrostan-B-one S-thioketal yields, respectively, (1 2a,4u,7a,17wtetramethyl-17,B-hydr-oxy-5 a-androstane (2) 4a,7u,17a-trimethyl-19-nor-17f3-hydroxy-5a-androstane (II), t

(3) 2a,4oc,7rx,170t-tetIaII1ethyl-19-110r-17fi-hYClIOXY-5aandrostane (II),

(4) 4o 7,17a-trimethy1-17/3-hydroxy-5fl-androstane (II),

(5) 2a,4u,7a,17a-tetramethy1-17B-hydroxy-5B-androstane.

(6) 4a,7a,17a-trimethyl-19-nor-17/3-hydroxy-5p-androstane (II),

(7) 2a,4a,7u,17u-tetramethyl-19-nor-17p-hydroxy-5fi-androstane (II).

EXAMPLE 26 4,7ot,17a trimtethyl 19-n0r-17/3-hydroxy-4-androsten-3- one 3-thi0ketal (4,7a,17a-lrimethyl-19-nortestosterone 3-thiaketal) To a solution of 2 g. of 4,7a,17or-t1imethyl-l9-nor-17B- hydroxy-4-androsten-3-one (II) in 6 ml. of acetic acid cooled to about C., 0.7 m1. of ethanedithiol and 0.7 ml. of borontrifluoride etherate is added. After standing at room temperature for about 20 minutes the reaction mixture is diluted to a volume of about 25 ml. with water and ice. The crystals are collected, washed with water and dried to yield 4,7a,l7a-trirnethyl-l9-nor-17fi-hydroxy- 4-androsten-3-oue 3-thioketal.

Following the procedure of Example 26 but substituting the following compounds for the starting material employed therein:

( 1 2a,4,7a,17a-tetramethyl-17,8-hydroxy-4-androsten-3- one (II),

(2) 2u,4,7a,17a-tetramethyl-19-nor-17/3-hydroxy-4- androsten-3-one (II) yields, respectively,

( l) Zoc,4,7oz, 17 Metramethyl-17,3-hydroxy-4-androsten-3- one B-thioketal and (2) 2a,4,7u,l7atetramethyl-19-nor-17fi-hydroXy-4- androsten-3-one 3-thioketal.

EXAMPLE 27 4,7o,17ot-trimethyl-19-nor-1 7 fi-hydroxy-4-androstene 4,7u,1 7a-trimethylestr-4-en-1 7 -01 11) To a solution of 1 g. of 4,7a,17a-trim-ethyl-l9-nor-17(3- hydroxy-4-androsten-3-one 3-thioketal, 3 ml. of distilled liquid ammonia, 15 ml. of ether and 5 ml. of tetrahydrofuran, 1 g. of sodium metal is added in small pieces. The steroid goes into solution rapidly as the sodium dissolves. The solution is refluxed for about 15 minutes and the blue color discharged by dropwise addition of absolute ethanol. A fast stream of nitrogen is passed through to aid in evaporating the solvents. After nearly all of the ammo mist and other solvents are removed, water is added. The resulting precipitate is collected, washed with Water, dried and recrystallized from acetone Skellysolve B to yield 4,7a,17a-trimethyl-19-nor-1718-hydroxy-4-androstene (II). The product can also be purified by chromatography through Florisil and recrystallization from acetone Skellysolve B or methanol.

Following the procedure of Example 27 but omitting tetrahydrofuran also yields 4,7a-dimethyl-19-nor-17fl-hydroxy-4-androstene (II).

Following the procedure of Example 27 but substituting the following compounds for the starting material employed therein:

(1) 2u,4,7a,l7a-tetramethyl-l7fi-hydroxy-4-androsten- 3-one 3-thioketal and (2) 2a,4,7 ,17a-tetrarnethyl-19-nor-17/3-hydroxy-4- androsten-3-one 3-thioketal yields, respectively,

( 1) 2a,4,7a,17a-tetramethyl-17fl-hydroxy-4-androstene (II) and (2) 2a,4,7a,17a-tetramethyl-19-nor-l7,8-hydroxy-4- androstene (II).

EXAMPLE 28 40,7a,17a-lrimethyl-19-n0r-1 7 B-hydroxy-S 18- androslane (II) the following representative compounds for the starting material employed therein:

(1) 2a,4,7 a, 17 a-tetramethyl- 17 B-hydroxy-4-androstene (II) and androstene (II) yields, respectively,

(1) 2a,4a,7a,17a-tetramethyl-17/3-hydroxy-518-androstane (II) and (2) 2a,4x,7a,17a-tetramethyl-19-nor-17B-hydroxy-5B- androstane (II).

EXAMPLE 29 4a,7a,17a-trimethyl-3a,1 7p-dihydroxy-Sfl-androstane (II) To a solution of 1 g. of 40,7u,17a-trimethyl-17fi-hydroxy-5fl-androstan-3-one (II) (prepared as in Example 17) in 100 ml. of tetrahydrofuran, 1.5 g. of lithium aluminum tri-t-butoxyhydride is added at about C. with stirring. The reaction mixture is stored at about 15 C. for about 18 hours. Dilute acetic acid is added until the inorganic materials coagulate. The original phase is decanted, dried over magnesium sulfate, filtered, concentrated to dryness, dissolved in an organic solvent and purified by chromatography with a Florisil Column to yield pure 4a,7a,17u-trimethyl 30,17B dihydroxy-S/B-androstane (II).

Following the procedure of Example 29 but substituting the following representative starting materials:

(1) 40,7a, 17oc-trimethyl-19-nor-17fi-hydroxy-55-androstan-3-one (II),

(2) 2u,4a,7a,17a-tetramethyl-17fl-hydroXy-5fl-androstan-3-one (II) and (3) 2a,4a,7a,17u-tetramethy1-19-nor-17fl-hydroxy-5B- androstan-3-one (II),

yields, respectively,

(1) 4a,7a,17a-trimethyl-19-nor-3u,17fl-dihydroxy-5pandrostane (II),

(2) 2a,4a,7a,17a-tetramethyl-3 a,17B-dihydroxy-5flandrostane (II) and (3) 20t,40t,7o,170L-ICtI'aIn6thy1-19-I10r-306,1713-dlhYdI'0XY- SB-androstane (II).

EXAMPLE 30 704,] 7,1 7-trimethyl-18-n0r-4,13-androstadien-3-0ne (III) Mill :0 1111.: (e 17,050

Nuclear magnetic resonance and infrared spectra support the proposed structure.

Analysis.-Calcd. for C I-1 0: Found: C, 83.34; H, 10.24.

Following the procedure of Example 30 but substituting the following representative compounds for the starting material employed therein:

(1 7a,17a-dimethyl-19-nor-17B-hydroxy-4-androsten-3- one (II),

(2) 7u,17a-dimethyl-3a,176-dihydroxy-4-androstene (II),

(3) 7a,17u-dimethyl-3fl,17fl-dihydroxy-4-androstene (II),

(4) 7a,17a-dimethyl-19-nor-3a,17B-dihydroxy-4-androstene (II),

(5 71x, 17a-.dimethyl- 19-nor-3 5,17p-dihydroxy-4-andro:

stene (II),

(6) 7a,17a-dimethyl-17B-hydroxy-4-androstene (II) (7) 7a,17a-dimethyl-19-nor-17/i-hydroxy-4-androstene (8) 70, 17a-dimethyl-19-nor-17B-hydroxy-5a-androstan- 3-one (II) (9) 7oz,17a-dimethyl-3a,17fi-dihydr-oxy-5tat-androstane (10) 7a,17a-dimethyl-19-nor-3 8, l'lfi-dihydroxy-SB- androstane (II), p

(11) 7a,17oc-dirnethyl-17/3-hydroxy-5a-androstane (II),

( 12) 7a,17u-dimethyl-19-nor-17fl-hydroxy-5fi-androstane 13) 211,71,17a-trirnethy1-19-nor-17B-hydroxy-4-andro sten-3-one (II),

(14) 2a,7m,17ot-trimethyl-3a,17B-dihydroxy-4-androstene (15) 2a,7a,17a-trimethyl-3,8,l7fl-dihydroxy-4-androstene (16) Za,7a,l7oc-tI'in'l6thyl-19-I1OI-3 a,17B-dihydroxy-4- androstene (II) (17) 20,7a,17u-trimethyl-19-nor-3fi,17B-dihydroxy-4- androstene (II),

(18) 20,7a,17u-trimethyl-17,8-hydroxy-4-androstene (II (19) 2a,7a,17a-trimethy1-19-nor-17B-hydroxy-4-androstene (II),

(20) 2a,7a,17tx-trimethyl-19-n0r-17B-hydr0xy-5u-androstan-3-one (II),

( 21) 2u,7u,17a-trimethyl-3oa,17fi-dihydroxy-5u-androstane (II) (22) 2a,7 a, 17 a-trimethyl-19-nor-3 [3, 17 B-dihydroxy-S pandrostane (II),

(23) 2a,7 x,17u-trimethyl-17/3-hydroxy-5wandrostane (24) 206,7,17a-trimethy1-19 -nor-17B-hydroxy-55-androstane (II) (25) 4,706,17OC-trlmethy1-19'I1OI"17fi-hydI'OXy-4-androsten- 3-one (II),

(26) 4,7, 17 a-trimethyl-3 a, 17 ,8-dihydroxy-4-androstene (27) 4,7u, l7a-trimethyl-3fl,17,8-dihydroxy-4androstene (28) 4,70,17a-trimethyl-l9-nor-3a,175-dihydroxy-4- androstene (II),

(29) 4,70,17a-trimethyl-19-nor-3 (3, 17fi-dihydroXy-4- androstene (II) (30) 4,7u,17a-trimethyl-17B-hydroxy-4-androstene (II),

(31 4,7 0c, 17a-trimethyl- 19-nor-17;3-hydroxy-4-androstene (32) 4a,7a,17u-trirnethy1-19-nor-17/3-hydroxy-5u-androstan-3 one (II), I

(3 3) 40,7oc, 1 7a-trimethyl-3 a, 17 B-dihydroXy-S a-androstane (II),

(34) 4u,7a,17m-trimethyl-19-nor-3f3,17,8-dihydroxy-56- androstane (II),

(35) 4a,7 x,17u-trimethyl-17fl-hydroXy-5o-androstane (36) 4a,7a,17u-trimethyl-19-nor-17fi-hydroxy-5p-androstane (II),

( 37) 2a,4,7o,17a-tetramethyl-19-nor-17B-hydroxy-4- androsten-3-one (II),

(38) 2a,4,7a,17a-tetramethyl-3oc,17B-dihydroxy-4-androstene (II) (39) 2a,4,7a,17a-tetramethyl-3fl,17fl-dihydroxy-4-androstene (II) (40) 2u,4,7a,17tx-tetramethyl-19-nor-3u,17{3-dihydroxy- 4-androstene (II),

(41) 2a,4,7a,17a-tetramethyl-19-nor-3B,17/3-dihydroxy-4- androstene (II) (42) 2a,4,7a,17a-tetramethyl-17,8-hydroxy-4-androstene (43) 2a,4,7a,17a-tetramethyl-19-nor-17B-hydroxy-4- androstene (II),

(44) 211,411,711,170t-tetramethy1-19-nor-17B-hydroxy-5aandrostan-3-one (II),

(45) 20,40t,70t,170t-tet-ramethyl-30t,17,B-dihydroxy-50tandrostane (II),

(46) 20,40,70t,170t-tetramethyl-19-nor-3fl,17(3-dihydroxy- Sfl-androstane (II),

(47) 20t,40t,70t,l70t-tetramethy1-l7 8-hydroxy-50t-androstane (II) and yields, respectively,

(1) 7a,17,17-trimethyl-18,19-dinor-4,13-androstadien-3- one (III),

( 2) 70t,17,17-trimethyl-18-nor-3a-hydroxy,4,l3-

androstadiene (III),

(3) 70,17,17-trimethyl-18-nor-3 8-hydroxy-4,13-

androstadiene (III),

.(4) 70,17,17-trimethyl-18,19-dinor-30t-hydr0xy-4,13-

androstadiene (III), (5 7a, 17, l7-trimethyl-l8,19-dinor-3fi-hydroxy-4,13-

androstadiene (III),

6) 7 0:,17,17-trimethy1-18-nor-4,13-androstadiene (III),

(7) 70,17,17-trimethyl-18,19-dinor-4,13-androstadiene (8) 7u,17,17-trirnethy1-1 8, 19-din0r-5a-androst-13-611- .3-.0ne (III),

(9) 701,17, 17-trimethyl-l 8-nor-3 a-50t-androst-13-ene (10) 7a,17,17-trimethyl-18,l9-dinor-3B-hydroxy-5flandrost-13-en (III),

(11) 70;,17,l7-trimethyl-18-nor-5u-androst-l 3-ene (III),

( 12) 7a,17,17trimethy1-18,19-dinor-SB-androst-13-ene (13) 20:,70t,17,17-tetramethyLl8,19-dinor-4,13-audrostadien-3-one (III),

(14) 200,700,17,17-tetramethyl-l8-nor-3a-hydroXy-4,13-

androstadiene (III),

( 15 2a,70z,17,17-tetrametl1yl-18-nor-3fi-hydroxy-4,13-

androstadiene (III),

' (16) :,70t,17,17-tetramethyl-18,19-dinor-3 B-hydroxy- 4,13-androstadiene (III), 17) 20:,70t,17,17-tetramethy1-18,19-dinor-3fi-hydroxy- 4,13-androstadiene (III), (18) 201,70,17,17 tetramethyl-18-nor-4,13-androstadiene (III), (l9) 2 0 ,70t,l7,l7-tetramethyl-l8,19-dinor-4, 13 -andr0stadiene (III),-

' 20) 2a,70z,'17,l 7-tetramethy1-18, 19-dinor-5a-andr0st- 13-en-3-one (III),

0 (21) 2 70:,17,17-tetramethyl-18-nor-30uhydroxy-50tandrost-13-ene (III) (22) 200,711,17,17-tetramethyl-l8,19-dinor-35-hydroxy- SB-androst-lB-ene (III), (23 20 7a,17,17-tetrameLhyl-18-nor-5a-androst-13 -ene 24 20l,7a,l7,l7 -tetramethyl-18,19-dinor-513-androst- (25 4,7 00,17,17-tetramethyl-18,19-dinor-4,13-androstadiandrostadiene (III), (28) 4,70z,17,17-tetramethyl-18,l9-dinor 4,13-androstadiene (III), (29) 4,70t,17,17-tetramethy1-l8,19-dinor 3 3 hydroxy- 4,13-androstadiene (III),

,(30) 4,701,17,17-tetramethyl-l8-nor-4,13 androstadiene j 31 "4:70;,17,17-tetramethyl-18,19-din0r-4,13- androstadiene (III), 7 Y (32) 401,700, 17, 17-tetramethyl-l 8,19-dinor-50t-andr0st- 13-en-3-one '(III) 33) 400,70,17,l7-tetramethyl-18-nor-30c-hydroxy-50tandrost-13-ene (III),

hydroxy- (34) 40,7a,17,17-tetramethyl-18,l9 -dinor-3fl-hydroxy- 5,8-androst-13-ene (III),

(3 5) 411,7, 17, 17-tetramethyl-18-nor-500-androst-13 -ene (36) 40,700,17,17-tetramethyl-18,l9-dinor-5fl-androst- 13-ene (III),

(37) 20,4,70t,17,17-pentamethyl-18,19-dinor-4,13-

andr0stadiene-3-one (III),

(3 8) 20,4,70,17,17-pentamethyl-18-nor--3 a-hydroxy- 4,13-androstadiene (III),

(39) 20,4,70,17,17 pentamethyl-18-nor--3,6-hydr0xy- 4,13-androstadiene (III),

(40) 20,4,70,17,17-pentamethyl-18,19-dinor-30thydroxy-4,l3-androstadiene (III),

(41) 206,4,706, 17 ,17-pentamethyl-18,19-dinor-3 flhydroxy-4,13-androstadiene (III),

(42) 20,4,70t,17,17-pentamethy1-18-nor-4,l3-

androstadiene (III),

(43) 20,4,70t,17,17-pentamethy1-18,19-dinor-4,13-

androstadiene (III),

(44) 20,40,70t,17,17-pentamethyl-18,19-dinor-50tandrost-13-en-3-one (III),

(45) 20,40,70t, 17, 17-pentamethyl-18-nor-3 0t-hydroxy- 50t-androst13-ene (III),

(46) 2a,40,700-17,17-pentamethyl-18,19-din0r-313- hydroxy-Sfi-androst-B-one (III),

(47) 20,40t,7u,17,17-pentamethy1-18-nor-50t-andr0st- 13-ene (III), and

(48) 20:,400,7a,l7,17-pentamethyl-l8,19-din0r-5fiandrost-l3-ene (III).

EXAMPLE 31 7a,]7,17-trimethyl-18-nor-3a-hydr0xy 4,13-androstadiene 3-dihydropyranyl ether (III) To 1.8 g. of 70,17,17-trimethyl-18-nor-30t-hydroXy-4,13- androstadiene (obtained in accordance with the procedure of Example 40) suspended in 10 ml. of dihydropyran and 50 ml. of ether, mg. of p-toluenesulfonic acid is added. The ether solution is stirred for about 16 hours, extracted successively with sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressureto yield a residue comprising 70,17,17-trimethyl- 18-i1or-30z-hydroxy-4,13-andr0stadiene 3 dihydropyranyl ether (III). Crystallization from aqueous methanol aflords pure 70,l7,17-trimethyl 18 nor 30 hydroxy-4,13- androstadiene 3-dihydropyranyl ether.

Following the procedure of Example 31 but substituting the following representative compounds for the starting material employed therein: i (1 700, 17,17-trimethyl-18,l9-dinor-3,B-hydroxy-4,13-

androstadiene (III),

(2) 700,17,17-trimethyl-18-nor-30t-hydroxy-500-androstl3-ene (III),

(3) 7a,17,17-trimethyl-18,19-dinor-3/9-hydroxy-5/3- androst-13ene (III),

(4) 20 7a,17,17-tetramethy1-18-nor-30t-hydroXy-4,13-

androstadiene (III),

( 5) 201,700,17,17-tetramethyl-18,l9-dinor-3 /8-hydroxy- 4,13-andr0stadiene (III),

(6) 200,711,17,l7-tetramethyl-l8-nor-3 Ou-hydrOXy-Saandrost-l3-ene (III),

(7) 200,7,17,17-tetramethyl-18,19-dinor-3fi-hydroxy- 5B-androst-13-ene (III),

(8) 4,70,17,l7-tetramethyl-18-nor-3 a-hydroXy-4, 13

androstadiene (III),

(9) 4,70t,17,17-tetramethyl-18,19-dinor-3fi-hydroxy- 4,13 -androstadiene III) 10) 412,706, l7,17-tetramethyl-18-nor-3 a-hydrOXy-Smandrost-13-ene (III),

( 1 1) 400,7 OL,17, 17 -tetramethyl-18, 19-din0r-3/3-hydroxy- SB-androst-lS-ene (III),

4,13-androstadiene (III),

3 l (13) 2a,4ot,7a,l7,l7-pentamethyl-l8,19-dinor-3fihydroxy-4,l3-androstadiene (III) and (14) 2a,4ot,7ot,17, l7-pentamethyl-18-nor-5a-androst l3-ene (III) yields the corresponding 3-dihydropyranyl ethers.

EXAMPLE 32 7a,] 7 ,1 7-trimethyl-18-n0r-3a-hydroxy-4J3 androstadiene 3-acetate (III) A mixture of 0.5 g. of 7a,17,17-trimethyl-18-nor-3ahydroxy-4,13-androstadiene, 0.5 ml. of acetic anhydride and 0.5 ml. of pyridine is refluxed for about 4 hours. Ice and water are added and the product is extracted with ether, washed with dilute hydrochloric acid, water, dilute sodium hydroxide, and again with water, and dried over sodium sulfate. The solvent is removed and the residue crystallized from aqueous methanol giving pure 7a,17,17- trimethyl-l8-nor 30c hydroxy 4,13 androstadiene 3-acetate. I

Following the procedure of Example 32 but substituting the following representative compounds. for the starting material employed therein:

(1) 7a,l7,l7trimethyl-l8,19-dinor-3 B-hydroxy4,13-

androstadiene (III),

l3-ene (III),

(3) 711,17,l7-trimethyl-18,l9-dinor-3B-hydroxy-5B- androst-lS-ene (III),

(4) 2a,7a,17,17-tetramethyl-18-nor-3 et-hydroxy-4, l 3- androstadiene (III),

(5) 2ot,7ot,17,17-tetramethyl-l8,l9-dinor-35-hydroxy- 4,13-androstadiene (III),

(6) 20,7ot,17,17-tetramethyl-l8-nor-3e-hydroxy-5otandrost-l3-ene (III),

55-androst-l3-ene (III), p (8) 4,7a,17,17-tetramethyl-18-nor-3ot-hydroxy-4,13-

androstadiene (III),

(9) 4,7a,17,17-tetramethyl-18,19-dinor-3fi-hydroxy- 4,13-androstadiene (III),

(10) 4a,7a,17,17-tetramethyl-18-nor-3a-hydroxy- 5oc-androst-13-ene (III),

(11) 4a,7a,17,17-tetramethyl-18,19-dinor-3phydroxy-SB-androst-l3-ene (III),

(12) 2a,4ot,7 a, 17 17-pentamethyl-1 8-nor-3 a-hydroxy- 4,13-androstadiene (III),

(13) 2a,4u,7a,17,17-pentamethyl-18-19,-dinor-3{3- hydroxy-4,13-androst-adiene (III) and (14) 2a,4a,7a,17,17-pentarnethyl-18-nor-5a-androst- 13-ene (III),

yields the corresponding 3-acetates.

In the same manner as in Example 32, the 3-cyclopentylpropionate, hydrocinnamate, butyrate, isobutyrate, va-lerate, isovalerate, hexanoate, octanoate, phenylacetate and other like esters of the representative compounds listed after Example 32 are prepared by reaction of the corresponding 3otand 3,8-hydroxy compounds with the appropriate acid anhydride or acid halide.

As indicated heretofore, the compounds of this invention are useful in therapy for their anabolic, anti-fertility, anti-androgenic, anti-estrogenic and hypocholesteremic (i.e., reducing blood cholesterol) activities, and particularly in the treatment of atherosclerosis and arteriosclerosis. Administration to mammals, including humans, depends on the particular compound involved, severity of the condition being treated and the individuals response to the medication. In general, a dose of about 5 to 1000 mg. of each of the compounds exemplified in Examples 1 to 32 and embraced within Formula III is given one to three times a day, and preferably about 50 to about 500 mg. thereof one to three times a day, in the treatment of conditions incident to the foregoing activities when incorporated in conventional pharmaceutical compositions.

The following examples illustrate the incorporation of 3.2 the active ingredients of this invention in pharmaceutical formulation.

EXAMPLE 33 Compressed tablets A lot of 10,000 compressed tablets, each containing 10 mg. of 17a,17,17-trimethyl-l8-nor-4,13-anrostadien-3- one is prepared from the following ingredients:

17ot,17,17 trimethyl 18-nor-4,13-androstadien-3- one Dicalcium phosphate 2500 Methylcellulose, USP (15 cps.) 65 Talc, bolted 450 Calcium stearate, fine powder 35 EXAMPLE 34 Hard gelatin capsules A lot of 1000 hard gelatin capsules, each containing 100 mg. of 20,7u,17,17-tetramethyl-18-nor-4,1B-androstadien-3-one is prepared from the following ingredients: G.

2a,7oc,l7,17 tetramethyl 18-nor-4,l3-androstadien- 3-one, micronized 100 Lactose Calcium stearate 2 Talc 3 EXAMPLE 35 Soft gelatin capsules A batch of 1000 soft gelatin capsules, each containing 50 mg. of 4,7a,17,17-tetramethyl-18-nor-4,13-androstadien-3-one and corn oil is prepared from the following materials:

G. 4.7a,17,17-tetramethyl-l8-nor 4,13 androstadien- 3-one, micronized 50 Corn oil q.s.

A uniform dispersion of the active ingredient in the corn oil is prepared and the dispersion filled into soft gelatin capsules by conventional means.

One capsule is given twice a day in the treatment of hypercholesteremia in adult humans.

EXAMPLE 36 Aqueous oral suspension An aqueous oral suspension containing in each 5 ml. 500 mg. of 2a,4,7a,17,17-pent-amethyl-18-nor-4,13-androstadien-3-one is prepared from the following materials:

2a,4,7a,17,17-pentamethyl 18 nor 4,13-androstadien-3-one, micronized g 1000 Methylparaben, USP g 7.5 Propylparaben, USP g 2.5 Saccharin sodium g 12.5 Cyclamate sodium g 2.5 Glycerin ml 3000 Tragacanth powder 100 One teaspoonful m1.) 3 times daily is employed in the treatment of hypercholesteremia in adult hum-ans.

EXAMPLE 37 Aqueous suspension for injection A suspending vehicle is prepared from the following materials:

G. Polyethylene glycol 4000 30 Potassium chloride 11.2 Polysorbate 80 2 Methylparaben 1.8 Propylparaben 0.2

Water for injection, q.s. to 1000 ml.

The parabens are added to a major portion of the Water and are dissolved therein by stirring and heating to 65 C. The resulting solution is cooled to room temperature and the remainder of the ingredients are added and dissolved. The balance of the water to make up the required volume is then added and the solution sterilized by filtration. The sterile vehicle thus prepared is then mixed with 50 g. of 7a,l7,17-trimethyl-l8,19-din0r-4,l3- androstadien-3-one which has been previously reduced to a particle size less than about microns and sterilized with ethylene oxide gas. The mixture is passed through a sterilized colloid mill and filled under aseptic conditions into sterile containers which are then sealed.

Each milliliter of this suspension contains 50 mg. of 7a,l7,l7-trimethyl 18,19 dinor- 4,13-androstadien-3- one. The suspension is used intramuscularly in l-ml. doses in the treatment of hypercholesteremi-a.

We claim:

1. 2a,7a,17,17 tetramethyl-18-nor-4,13-androstadien-3- one. a

2. 201,711,17,l7-tetramethyl-l8,l9-dinor-4,l3-androstadien-3-one.

3. 4,7a,17,17-tetramethyl-18-nor-4,13-androstadien-3 one.

4. 4,7ot,17,17-tetramethyl-18,19-din0r-4,13-androstadien-3-one.

5. Compounds of the formula wherein R is selected from the group consisting of hydrogen and methyl and R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon 34 carboxylic acid containing from one to twelve carbon atoms, inclusive.

9. 7a,17,17-trimethyl-18-nor-3fi-hydroxy-5a-androstan- 13-ene.

10. 7a,l7,l7-trimethyl-18,19'-dinor-3,B-hydroxy-Sa-androstan- 1 3-ene-3 -ace-tate.

11. Compounds of the formula wherein R is selected from the group consisting of hydrogen and methyl.

12. 70c, 17, 17-trimethyl-1 8, l9-dinor-4, 1 3-androstadiene. 13. A therapeutic composition comprising: about '5 to about 1000 mg. of a compound selected from the group consisting of those having the formulae CH p113 on. 0H;

Ri O=(/ "CH3 on on;

R. I Rr-fi O=\/ "CH3 CH3 CH 1 (\l RO- 0H3 V: D and on. on.

CH3 CH3 wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one through twelve carbon atoms and R and R are selected from the group consisting of hydrogen and methyl.

References Cited Caspi et al., Canadian Jour. Chem. (1963), vol. 41, pp. 2294- relied on.

Dorfiman, Steroids (1963), p. 191.

Segalofi et al., Steroids (1964), No. 3 pp. 436-38.

ELBERT ROBERTS, Primary Examiner.

LEWIS GO'ITS, Examiner.

UNITED STATES PAIEN'I OFFICE CERTIFICATE OF CORRECTION Patent NO 3 1 ,411 September 12 1967 J Allan Campbell et al It is h y certi ed that error appears in the above numbered patent quiring rectio nd that the said Letters Patent should read as corrected below.

Column 1 line 15 to Z5 the formula should appear as shown below instead of as in the patent same column 1 lines 38 to 40 the formula should appear as shown below instead of as in the patent oz 02 Q and C column 5 line 27 for "butyoxyhydride" read butoxyhydride column 5 line 3 for "Forumla" read Formula column 8 line 10 for "toluenesulfanic" read toluenesul fonic line 23 for "hydrox Com undg" read hydroxy compounds column 10 line 32 or "1200" read 1220 e column 14 line 45 for "-3 read 3 one l ine 7l for "-3-one (II) yields respectively read 3 one 3 thioketal column 17 line 32 for dimenthyl" read dimethyl column 18 line 8 for "triemthyl" read trimethyl line 11 for "dimehyl read dimethyl column 20 line 51 for (11)" read (II) column 22 lines 7 and 8 for "-androsane" read andro stane column 29 line 15 for "hydroxy 4 l3 read hydroxy l l 3 line 27 for "3 5d-" read 3 L-hydroxy- 5a l ine 60 "to tamethyl" read tetramethyl column 30 l ine o2 for "-3001" read 3 1 column 31 line 48, for "18l9,-" read -l8-l9- column 32, line 7, for "anrostadien-" read androstadiencolumn 34 lines 43 to 54, the formula should appear as shown below instead of as in the patent:

Signed and sealed this 18th day of March 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

14. A METHOD FOR REDUCING BLOOD CHOLESTEROL IN MAMMALS COMPRISING: ADMINISTERING TO MAMMALS A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAE 